Hydroxyphenyl derivatives and biological applications thereof

ABSTRACT

The invention relates to hydroxyphenyl derivatives of formula (I); and uses thereof as anti-bacterial and/or anti-parasitic agents.

This application is a continuation of application Ser. No. 12/226,281(allowed), filed Oct. 14, 2008 (published as US 2010-0041658 A1), whichis a U.S. national phase of International Application No.PCT/IB2007/002127, filed Apr. 16, 2007, which designated the U.S. andclaims priority to EP 06290611.0, filed Apr. 14, 2006, the entirecontents of each of which are hereby incorporated by reference.

The invention relates to hydroxyphenyl derivatives and a process formaking the same. It also relates to the biological applications thereof,particularly as anti-bacterial and/or anti-parasites agents.

The invention more particularly relates to Triclosan derivatives.Triclosan (TCL) 5-chloro-2-(2,4-dichloro-phenoxy)-phenol (A) is abroad-spectrum biocide that has been in use for over 30 years, mainly asa component of antimicrobial wash products in health-care settings, offormula (A)

More recently, Triclosan has found extensive use in consumer productssuch as toothpaste, mouthwashes, deodorants, hand soaps, and lotions. Itis also incorporated in children's toys, cutting boards, and the plasticfilm used to wrap meat products. Until recently, it was thought thatTriclosan, being a small hydrophobic molecule, was absorbed viadiffusion into the bacterial cell wall and that unspecific disruption ofthe cell wall was the mechanism by which Triclosan exhibited itsantibacterial activity. However, the first evidence that Triclosaninhibits fatty acid biosynthesis came when a strain of E. coli resistantto Triclosan was isolated, and the resistance was mapped to the fabIgene which codes for the E. coli trans enoyl-acyl carrier proteinreductase (ENR). Fatty acid biosynthesis in bacteria is essential to theproduction of a number of lipid-containing components including the cellmembrane. The bacterial fatty acid synthase system (FASII) utilizesdiscrete monofunctional enzymes that operate in conjunction with acylcarrier protein (ACP)-associated substrates. Mammalian fatty acidsynthase (FASI) differs from FASII in that lipid biosynthesis ismediated by a single multifunctional enzyme-ACP complex. The differencesin prokaryote and eukaryote fatty acid biosynthesis offer an attractiveopportunity for selective FASII inhibition. FabI is an enoyl-ACPreductase that catalyzes the ultimate and rate-limiting step of thechain elongation process of FASII. The reaction involves the conjugatereduction of an enoyl-ACP to the corresponding acyl-ACP using thecofactor NAD(P)H as a hydride source.

Subsequently, extensive biochemical and structural studies have beenperformed to substantiate Triclosan as a specific E. coli FabIinhibitor. Two ENR isoforms, FabK and FabL, have been discovered in thegram-positive bacteria, Streptococcus pneumoniae and Bacillus subtilis,respectively. FabK is resistant to Triclosan, whereas FabL is reversiblyinhibited by Triclosan. Triclosan also directly inhibits the FabI fromStaphylococcus aureus, Haemophilus influenzae, the ENR fromMycobacterium tuberculosis, InhA, and the ENR from Plasmodiumfalciparum, the malarial parasite.

Since the discovery of FabI as the bacterial target of Triclosan,several specific inhibitors not structurally related to TCL have beenreported, few of them displaying antibacterial activities.

Some analogues of Triclosan itself have been described in separatechemo-enzymatic studies of the Triclosan mode of action against FabI.Especially, the antibacterial activity of several 2-hydroxydiphenylethers hexachlorophene and 2-hydroxydiphenylmethanes as well as5-alkylated, -fluorinated or -formylated derivatives have beendetermined. On the other hand, before the discovery of the potentinhibition of FabI by TCL, some modifications of the dichlorophenol partof TCL were also reported. For instance broad spectrum, but non specificantibacterial and antifungal derivatives were reported by introducing apyridine instead of a phenyl ring.

In contrast to TCL, which displays a broad spectrum biocidal effect withno distinction between microorganisms, new TCL derivatives that wouldtarget only the microorganisms which carry the FabI enzyme such as S.aureus or E. coli would be selective antibacterial or antiparasiticagents of interest with no antibacterial effect or selective pressureagainst other bacterial species.

The inventors have found that specific substitutions of hydroxyphenylderivatives having triclosan basic structure lead to derivatives thatsurprisingly display a selective and narrow spectrum of activity againstrelevant pathogens, particularly bacteria or parasites.

An object of the invention is then to provide new substitutedhydroxyphenyl derivatives which selectively inhibit the growth ofbacteria carrying Fab enzymes such as FabI, FabL, FabK, InhA.

Another object of the invention is to provide a process for thesynthesis of said derivatives.

Still another object is to take advantage of the biological propertiesof said molecules to provide means, i.e. pharmaceutical compositions andmethods, particularly useful for treating microbial infections.

The hydroxyphenyl derivatives of the invention have formula (A)

wherein

-   -   R1 is aryl, heterocycle, aliphatic heterocycle, cycloalkyl, all        having one or several cycles, alkyl, all substituted or not by        one or several R identical or different, selected in the group        comprising, H, alkyl, alkenyl, alkynyl, aryl, heterocycle,        aliphatic heterocycle, fluoro-alkyl, halogen, COOH, CO₂R_(a),        COR_(a), CONR_(a)R_(b), OCOR_(a), CN, OR_(a), aryloxy        NR_(a)R_(b), CR_(a)═NOR_(b), NR_(a)-aryl, NR_(a)COR_(b),        NR_(a)COOR_(b), OCONR_(a)R_(b), NR_(a)CONR_(b)R, SR_(a),        SO₂R_(a), SO₂NR_(a)R_(b), NR_(a)SO₂R_(b), NR_(a)C(S)NR_(b)R_(c),    -   R2 is aryl, aryloxy, heterocycle, aliphatic heterocycle,        cycloalkyl, all having one or several cycles, H, alkyl, alkenyl,        alkynyl, halogen, fluoro-alkyl, fluoro-alkenyl, OCF₃, OCHF₂,        NR_(a)R_(b), CO₂R_(a), COR_(a), OR_(a), CONR_(a)R_(b),        CR_(a)═NOR_(b), SR_(a),    -   all being substituted or not by one or several R, identical or        different, being such as above defined,    -   R_(a) and R_(c), identical or different, being H or as above        defined with respect to R,    -   two adjacent R, or two adjacent R_(a) and/or R_(b), and/or R_(c)        optionally forming together a cycle    -   X=O or S    -   Y represents C(O)R, CO(O)R, C(S)R, C(S)OR, C(O)NR_(a), R_(b),        phosphate, P(O)(OR)₂, CH₂OR, or any labile group which may act        as a prodrug to regenerate the free phenol,    -   Z1, Z2, Z3, identical or different, are halogen or H, and the        pharmaceutically acceptable salts, the organic and mineral        salts, as well as the racemic derivatives and each unique non        racemic derivatives, in case the derivatives of formula (A) have        one or more chiral centers, both the cis (Z) and trans (E)        isomers in case the derivatives of formula (A) have unsaturated        carbon=carbon double bonds, both forms of tautomers in cases the        derivatives of formula (A) may exist in tautomeric forms,        provided that with respect to formula (A), when R2 is H, C1 to        C26 alkyl substituted or not by OH, NH2, SH, halo or CO₂H or OR,        SR, NHR, COOR, COR, CONHR, SO₂NHR, R being H, C1 to C26        substituted or not by OH, NH₂, SH, halo or CO₂H; Y═H; X═O; Z1,        Z2 Z3 are H; and R1 is a group of formula,

if T1 and T5 are independently N or C—R, R being H, methyl, ethyl, halo,then

-   -   either    -   T2 or T4 are different from CH or N,    -   or    -   T3 is different from N or C—R, wherein R represent H, methyl,        ethyl, halo, nitro, hydroxy, amino, amido or a methyl or an        ethyl group substituted with halo, nitro, hydroxy, amino, amido;        if T2 and T4 are independently CH or N, then    -   either    -   T1 or T5 are different from N or C—R, R being H, Me, ethyl,        halo,    -   or    -   T3 is different from N or C—R, wherein R represent H, methyl,        ethyl, halo, nitro, hydroxy, amino, amido or a methyl or an        ethyl group substituted with halo, nitro, hydroxy, amino, amido;        if T3 represent N or C—R, wherein R represent H, methyl, ethyl,        halo, nitro, hydroxy, amino, amido or a methyl or an ethyl group        substituted with halo, nitro, hydroxy, amino, amido; then.    -   either

T1 or T5 are different from N or C—R, R being H, Me, ethyl, halo,

-   -   or    -   T2 or T4 are different from CH or N.

When R1 is an heterocycle and more specifically a pyridine, theinvention also includes the N-oxide form.

“Alkyl” as applied herein means an optionally substituted alkyl groupand preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl andt-butyl, pentyl, n-pentyl, isopentyl, neopentyl, hexyl and octyl.

“Alkoxy” and “thioalkyl” mean any O or S atom substituted by asubstituted or not alkyl group.

“Aryloxy”, “thioaryl”, “NH-aryl” mean any O, S, N substituted by asubstituted or not aryl, or heterocyclic group.

“Aryl” (or “Ar”) means phenyl or naphtyl optionally substituted by R.

“Alkenyl” and “alkynyl” mean optionally substituted C═C or C≡C groups.

“Halogen” or “halo” means F, Cl, Br, and I.

“Aliphatic heterocycle” or “heterocycle” indicates an optionallysubstituted five or six membered monocyclic ring, or a nine orten-membered bicyclic ring containing one to three heteroatoms chosenfrom the group of nitrogen, oxygen and sulfur, which are stable andavailable by conventional chemical synthesis. Illustrative heterocyclesare for example selected in the group comprising benzofuryl,benzimidazolyl, benzopyranyl, benzothienyl, furyl, imidazolyl,indolinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl,pyrrolidinyl, tetrahydropyridinyl, pyridinyl, thiazolyl, thienyl,quinolinyl, isoquinolinyl, and tetra- and perhydro-quinolinyl andisoquinolinyl, pyrazinyl, pyrazidinyl, triazinyl, purine, indolyl,indazolyl, pyrimidinyl, pyridonyl, oxazolyl, tetrahydropyranyl,tetrahydrofuranyl.

The invention more particularly relates to hydroxyphenyl derivativeshaving formula (I)

wherein

-   -   R1 is phenyl or a 6 membered monocyclic nitrogenous heteroaryl        of formula

-   -   Z4, Z5, Z6, Z7 and Z8 independently are C or N with a maximum of        three N, R1 being possibly substituted by 1 to 3R identical or        different, R being selected from the group comprising H, C₁-C₈        alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, 5 or 6 membered monocyclic        heteroaryl or aliphatic heterocycle containing 1 to 3        heteroatoms selected from N, O and S, COOR_(a), COR_(a),        CONR_(a)R_(b), OCOR_(a), CN, OR_(a), NR_(a)R_(b),        CR_(a)═NOR_(b), NR_(a)COR_(b), NR_(a)COOR_(b), OCONR_(a)R_(b),        NR_(a)CONR_(b)R_(c), SR_(a), SO₂R_(a), SO₂NR_(a)R_(b),        NR_(a)SO₂R_(b) and NR_(a)C(S)NR_(b)R_(c), all being possibly        substituted by R′, or R is C₁-C₄ fluoro-alkyl, or R is fluor        when R1 is phenyl, or R is halogeno when R1 is nitrogenous        heteroaryl,    -   R2 is phenyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,        C₁-fluoro-alkyl, C₂-C₄ fluoro-alkenyl, OR_(a), SR_(a), all being        possibly substituted by 1 to 3 identical or different R′,    -   R_(a), R_(b) and R_(c), identical or different, are selected        from the group consisting of H, C₁-C₈ alkyl, C₂-C₈ alkenyl,        C₂-C₈ alkynyl, phenyl, heteroaryl and aliphatic heterocycle as        defined above for R2, the heteroaryl and the heterocycle being        possibly formed with the carbon and nitrogen atoms to which        R_(a), R_(b) and R, are linked,    -   R′ is selected from the group comprising heteroaryl and        aliphatic heterocycle as defined above for R2, C₁-C₈alkyl,        CH₂CO₂R″, CO₂R″, COR″, CONR″R′″, OCOR″, OR″, NR″R′″, NR″COR′″,        NR″COOR′″, OCONR″R′″, NR″CONR″R′″, NR″SO₂R′″, SO₂R″, NR″SO₂R′″,        halogen and CN, R″ and R′″, identical or different, are H, C₁-C₈        alkyl or form together a 4 to 6 membered heterocycle with 1 to 3        heteroatoms selected from N, O and S,    -   Y represents H or a labile chemical group able to regenerate in        vivo the free phenol selected from the group consisting of        C(O)R_(a), C(O)OR_(a), C(O)NR_(a), R_(b), P(O)(OH)₂, and        COCHR_(a)NR_(b)R_(c),    -   Z1 and Z3, identical or different, are halogen or H,    -   Z2 is fluor or H,        provided that    -   either Z2 is fluor and all the other definitions are as defined        above,    -   or Z6 is a carbon atom substituted by R as defined above, R        being different from H, alkyl, halogen, NH₂, OH, CONH₂ or fluoro        alkyl and all the other definitions are as defined above,    -   or Z4 or Z5, or Z7 or Z8 are carbon atoms substituted by        NR_(a)R_(b) or OR_(a) being different from H and all the other        definitions are as defined above,    -   or Z5, or Z7, is a carbon atom substituted by R, R being        different from H and all the other definitions are as defined        above,    -   or R2 is a C₁-C₈ alkyl-heteroaryl radical or a C₁-C₈        alkyl-OR_(a) and all the other definitions are as defined above,        and the pharmaceutically acceptable organic and mineral salts,        as well as the racemic derivatives and each unique non racemic        derivatives, in case the derivatives of formula (I) have one or        more chiral centers, both the cis (Z) and trans (E) isomers in        cases the derivatives of formula (I) have unsaturated        carbon=carbon double bonds, and any N-oxide form of the        derivatives.

In formula I:

“C₁-C₈ alkyl” as applied herein means linear, branched or cyclichydrocarbon groups having 1 to 8 carbon atoms preferably methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl,isopentyl, neopentyl, hexyl, octyl, cyclopropyl cyclobutyl, cyclopentyl,cyclohexyl;

“C₂-C₈ alkenyl and “C₂-C₈ alkynyl” as applied herein means linear,branched or cyclic hydrocarbon groups of 2 to 8 carbon atoms, having atleast one double bond or one triple bond and preferably, ethenyl,propenyl, butenyl, cyclohexenyl, ethynyl, propargyl, butynyl;

C₁-C₄ fluoro alkyl and C₂-C₄ alkenyl” means a C₁-C₄ alkyl or C₂-C₄alkenyl group substituted by 1 to 7 fluorine atoms.

“Halogen” means F, Cl, Br, and I;

“Heteroaryl” and “Aliphatic Heterocycle” as applied herein means a 5-10membered aromatic or non-aromatic mono or bicyclic ring, containing atleast one heteroatom selected from N, O and S. Illustrative heterocyclesare for example selected in the group comprising benzofuryl,benzimidazolyl, benzopyranyl, benzothienyl, furyl, imidazolyl,indolinyl, azetidinyl, morpholinyl, piperidinyl, piperazinyl,oxazolidinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, tetrahydropyridinyl,pyridinyl, thiazolyl, thienyl, quinolinyl, isoquinolinyl, and tetra- andperhydro-quinolinyl and isoquinolinyl, pyrazinyl, pyrazidinyl,triazinyl, triazolyl, tetrazolyl, indolyl, indazolyl, pyrimidinyl,pyridonyl, oxazolyl, isoxazolyl, isothienyl, quinazolinyl, oxadiazolyl,thiadiazolyl, phtalimidyl.

“C₁-C₈ alkyl-heteroaryl” means a C₁-C₈ alkyl such as above definedsubstituted with one heteroaryl group such as above defined.

“C₁-C₈ alkyl-OR_(a)” means a C₁-C₈ alkyl such as above definedsubstituted with one OR_(a) group such as above defined, OR_(a) beingdifferent from OH.

According to a first family, the invention particularly relates toderivatives of formula (I) wherein R1 is a 6-membered monocyclicheteroaryl group such as above defined. Preferably, the nitrogeneousheteroaryl with one or 3 nitrogen atoms is selected in the groupcomprising a pyridine, a pyrimidine, a pyridazine, a pyrazine or atriazine.

In particularly preferred derivatives of said first family, R1 is asubstituted heteroaryl group such as above defined.

Advantageously, the nitrogeneous heteroaryl group is substituted by oneor several substituents selected in the group comprising F, COR_(a), OR,NR_(a)R_(b), alkynyl, SO₂R_(a), NR_(a)SO₂Rb, SO₂NR_(a)R_(b),NR_(a)COOR_(b) and CR_(a)═NOR_(b).

According to a second family, the invention particularly relates toderivatives of formula (I) wherein R1 is a phenyl group.

Particularly preferred derivatives of said second family are substitutedby one or several substituents selected in the group comprising F,COR_(a), OR_(a), NR_(a)R_(b), alkynyl, SO₂R_(a), NR_(a)SO₂R_(b),SO₂NR_(a)R_(b), NR_(a)COOR_(b) and CR_(a)═NOR_(b).

In a preferred embodiment, in the above defined derivatives of saidfirst and/or second family, Z2 is fluor. The fluorine atom beingadvantageously positioned in para of the OH group of compound of formulaI when Y=H to prevent the in vitro or in vivo oxidation of the phenoliccompound into the corresponding quinone.

According to another embodiment, Z6 is a carbon atom substituted by R asdefined above, R being different from H, alkyl, halogen, NH₂, OH, CONH₂,or fluoro alkyl and all the other definitions are as defined withrespect to formula (I).

According to still another preferred embodiment, Z4 or Z5, or Z7 or Z8,are carbon atoms substituted by NR_(a)R_(b) or OR_(a), OR_(a) beingdifferent from OH and all the other definitions are as defined withrespect to formula (I).

In a further embodiment, Z5 or Z7 is a carbon atom substituted by R, Rbeing different from H and all the other definitions are as defined withrespect to formula (I).

According to an other embodiment family, the invention particularlyrelates to derivatives of formula (I) wherein, R2 is aC₁-C₈alkyl-heteroaryl or a C₁-C₈alkyl-OR_(a), OR_(a) being differentfrom OH.

In a more preferred embodiment, Y represents H.

Also included in this invention are compounds in which Y is differentfrom H, Y being a labile chemical group able to regenerate in vivo thefree phenol compounds of formula I with Y being H such C(O)R_(a),C(O)OR_(a), C(O)NR_(a), C(O)NR_(a)R_(b), P(O)(OH)₂, COCHR_(a)NR_(b)R_(c)

It will be understood that the above defined embodiment can be used incombination with any one of the other defined embodiments.

The invention also relates to a process for making the above definedderivatives.

In a first embodiment of the invention, said process comprises the stepsof

-   a) reacting with AR1, a phenol derivative of formula (II)

-   -   wherein R1, R2 and Z1, Z2, Z3 are as above defined, R3        represents an alkyl group, and A is a reactive group such as an        halogen or a nitro capable of reacting with the OH group of (II)        under basic conditions known to the one skilled in the art to        give a derivative of formula (III)

-   b) reacting the protected phenol derivative of formula (III) with    any suitable Lewis acid for example BBr₃ or BCl3, under conditions    to give the desired derivatives of formula (I).

To obtain derivatives wherein R2 represents a functional group, thedesired function is introduced prior removal of R3.

Alternatively, the derivatives of formula (I) are advantageouslyobtained from the protected phenols of formula (II) by introducing a R4group different from R3=alkyl which can be smoothly remove in a nonrestrictive manner by hydrogenation, acidic conditions or treatment withfluoride derivatives to generate compound of formula (I) according to aprocess comprising:

-   -   a) reacting the protected phenol derivative of formula (II) with        TosCl under conditions to give a derivative of formula (IV)

-   -   b) reacting the derivative of formula (IV) with any suitable        Lewis acid such as BBr₃, BCl₃ under appropriate conditions to        give a derivative of formula (V)

-   -   c) treating the derivative of formula (V) under basic or acidic        conditions, to introduce R4, R4 being a protecting group        different from a linear alkyl, such as benzyl, BOM, SEM, MOM,        MEM, TBDMS, THP or analogs, resulting in a derivative of formula        (VI),

-   -   d) reacting said derivative of formula (VI) under appropriate        conditions, to obtain the removal of Tosyl group, resulting in        of a derivative of formula (VII)

-   -   e) reacting the derivative of formula (VII) thus obtained with        AR1 such as above defined to obtain a compound of formula (III′)

-   -   and    -   f) deprotecting the phenol group to obtain the desired        derivative of formula (I) with Y representing H, wherein R2 is        functionalized if desired as above mentioned, optionally from        derivative of formula (VI).

According to a second embodiment, compounds of formula (I) with Z2=F canbe obtained according to the following synthetic scheme 1 by a processcomprising:

-   -   a) reacting the bromophenol of formula (VIII) first with AR1        such as above defined and a base to generate a derivative of        formula (IX); then reacting derivatives of formula (IX) with a        suitable palladium catalyst with its ligands, chosen from the        group, as non restrictive examples of Pd(PPh₃)₄ or        Pd(dppf)Cl₂.DCM, a suitable base such as potassium carbonate or        cesium carbonate and R2B, R2 being as above defined and B being        a boronic ester residue to obtain the derivatives of formula        (X):

-   -   or alternatively,    -   b) compound of formula (VIII) is protected with a benzyl group        prior to be reacted with a palladium catalyst in the presence of        a base and a boronic reactant of formula R2B, such as defined        above, to generate the benzylated derivative (XI), debenzylation        with palladium on charcoal and hydrogen generates the free        phenol (XII) which is then reacted with AR1 according to step        the process described above to generates derivatives of formula        (X)

-   -   c) finally, compounds of formula (X) are dealkylated using Boron        tribromide to generate derivatives of formula (I) according to        scheme 3.

According to a third embodiment, the invention also comprises a processwherein a compound of formula (XIII), corresponding to compounds offormula (III),(VI),(VII),(X) or (I) in which R2 is vinyl and R5 is R3 orR4 as above defined or H, is reduced by hydrogenation with palladium oncharcoal (according to scheme 4) to give the R2=ethyl compoundderivative (XIV), corresponding to compounds of formula(III),(VI),(VII),(X) or (I) which can be further deprotected accordingto the above process when R5=R3 or R4.

According to a fourth embodiment, the process of the invention formaking a compound of formula (I) consists of converting, derivatives offormula I in which Y═H advantageously by methods known by one skilled ofthe art into a compound in which Y is C(O)R_(a), CO(O)R_(a), C(O)NR_(a),R_(b), P(O)(OH)₂, and COCHR_(a)NR_(b)R_(c).

As illustrated by the examples given hereinafter, the above disclosedphenol derivatives of the invention have valuable biological properties.

They are particularly useful as antibacterial agents having a selectivespectrum of activity in vitro against standard bacterial strains whichare used to screen for activity against pathogenic bacteria. Notably,the derivatives of the present invention show a high activity againstbacteria carrying Fab enzymes such as FabI, FabL, FabK, InhA.Particularly against Staphyloccus aureus including multiresistantstrains, Escherichia coli, Helicobacter pylori and also bacteria such asMycobacterium tuberculosis carrying homologous Fab enzymes such as InhAor other organisms such as Plasmodium falciparum. Said derivatives arethen particularly suitable as active principle of drugs.

The invention thus also relates to compositions comprising a phenolderivative of formula (I) such as above defined for use as drug.

It also relates to pharmaceutical compositions comprising a phenolderivative of formula (I) such as above defined in combination with apharmaceutically acceptable carrier.

Said pharmaceutical compositions are formulated to be administered underoral, injectable, parental routes, with doses appropriate for thepatient to be treated.

The compositions of the invention may conveniently be presented in unitdosage form and may be prepared by any methods well known in the art ofpharmacy. The amount of active ingredient which can be combined with acarrier material to produce a single dosage form will generally be thatamount of the compound which produces a therapeutic effect.

A suitable daily dose of the compounds of the invention will be thatamount of the compound that is the lowest dose effective to produce atherapeutic effect. Generally, topical, intravenous and subcutaneousdoses of the compositions of this invention for a patient, when used forthe indicated effects, will range from about 0.0001 to about 100 mg perkilogram of body weight per day, given in one or several dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

Said compositions are particularly useful to treat human or animalinfections by microbial pathogens such as E. coli, H. pylori or S.aureus or M. tuberculosis and parasites such as Plasmodium falciparum.

Said compositions are also useful in multitherapy, in combination withother drugs, for example with antibiotics.

The invention also relates to a method of treatment of microbialinfections which comprises administering to a patient in need thereof anefficient amount of a pharmaceutical composition such as above defined.

Other characteristics and advantages of the invention are given in theexamples hereafter wherein it is referred to FIGS. 1 and 2, whichrepresent, the protection of mice against the lethal effect of bacterialmultiplication.

Synthesis of Example Compounds

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded ateither 300 or 400 MHz, and chemical shifts are reported in parts permillion (8) downfield from the internal standard tetramethylsilane(TMS). Abbreviations for NMR data are as follows: s=singlet, d=doublet,t=triplet, q=quadruplet, qt=quintuplet, se=sextuplet, m=multiplet,dd=doublet of doublets, dt=doublet of triplets, br=broad. J indicatesthe NMR coupling constant measured in Hertz. CDCl₃ isdeuteriochloroform, DMSO-d⁶ is hexadeuteriodimethylsulfoxide, and CD₃ODis tetradeuteriomethanol. Mass spectra were obtained using eitherelectrospray (ESI) or atmospheric pressure photoionization (APPI)techniques. Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thinlayer plates were used for thin layer chromatography. Flashchromatography was carried out on Flashsmartpack cartridge, irregularsilica 40-60 μm or spherical silica 20-40 μm

TLC refers to thin layer chromatography, MS refers to mass spectra, HPLCrefers to high pressure liquid chromatography, NMR refers to nuclearmagnetic resonance, APT refers to attached proton test, HSQC refers toheteronuclear single quantum correlation, NOESY refers to nuclearOverhauser enhancement spectroscopy.

Certain reagents and radical groups are abbreviated herein areabbreviated herein. t-Bu refers to the tertiary butyl radical, Bocrefers to the t-butyloxycarbonyl radical, Ph refers to the phenylradical, Cbz refers to the benzyloxycarbonyl radical, Bn refers to thebenzyl radical, Me refers to methyl, Et refers to ethyl, Ac refers toacetyl, Nph refers to 1- or 2-naphthyl and cHex refers to cyclohexyl.DCC refers to dicyclohexylcarbodiimide, DMAP refers to4-dimethylaminopyridine, EDC refers to1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride, HOBtrefers to 1-hydroxybenzotriazole, THF refers to tetrahydrofuran, DIEArefers to diisopropylethylamine, DEAD refers to diethylazodicarboxylate, PPh₃ refers to triphenylphosphine, DIAD refers todiisopropyl azodicarboxylate, DME refers to dimethoxyethane, DMF refersto dimethylformamide, NBS refers to N-bromosuccinimide, Pd/C refers to apalladium on carbon catalyst, PPA refers to polyphosphoric acid, DPPArefers to diphenylphosphoryl azide, BOP refers tobenzotriazol-1-yloxy-tris(dimethyl-amino)phosphoniumhexafluorophosphate, TEA refers to triethylamine, TFA refers totrifluoroacetic acid, PCC refers to pyridinium chlorochromate, TBAFrefers to tetrabutyl ammonium fluoride, Tos refers to Tosyl and TosClrefers to tosyl Chloride, BOM refers to p-methoxybenzyl, MOM refers tomethoxy-methyl, MEM refers to methoxy-ethoxymethyl, SEM refers totrimethyl-silyl-ethoxymethyl, THP refers to tetrahydropyranyl, TSIrefers to triethylsilyl, TBDMS refers to tButyl-dimethyl-silyl, DCMrefers to dichloromethane, CAN refers to acetonitrile, Pet ether refersto petroleum ether.

EXAMPLE 1 2-[(3-amino-6-chloropyridin-2-yl)oxy]-5-propylphenol a)2-chloro-6-(2-methoxy-4-propylphenoxy)pyridin-3-amine (A) and6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine (B)

To a suspension of K₂CO₃ (2.4 mmol; 331 mg) in anhydrous DMF (1 mL)under argon, was added 2-methoxy-4-propylphenol (1 mmol; 0.16 ml)followed by 2.6-Dichloro-3-nitropyridine (1 mmol; 176 mg). The reactionmixture was stirred at 40° C. over 48H. After quenching with NaOH (0.1N;3 mL), the mixture was extracted with ethyl acetate (3*3 mL). Combinedorganic phases were dried over Na₂SO₄, concentrated in vacuo, to give ayellow solid (480 mg; 1.49 mmol; 74%), used without furtherpurification. 240 mg of that solid (0.75 mmol) were dissolved in THF (3mL) under argon. Palladium on activated carbon (50 mg) was added thenthe reaction was flushed twice with hydrogen, then left to stirovernight. The reaction mixture was then filtered on celite, and thenrinsed with ethyl acetate (3*5 mL), to give a mixture of regioisomers.After purification by preparative TLC (dichloromethane), theregioisomers were isolated as light yellow oils. (A: 40 mg, 0.14 mmol,B: 30 mg, 0.1 mmol, global yield: 32%)

A: ¹H NMR (CDCl₃) δ (ppm): 7.08 (d, 1H, J=8.3 Hz); 6.97 (d, 1H, J=7.9Hz); 6.76 (m, 2H);

6.59 (d, 1H, J=8.5 Hz); 2.59 (t, 2H, J=7.6 Hz); 1.65 (se, 2H, J=7.4 Hz);0.98 (t, 3H, J=7.2 Hz).

B: ¹H NMR (CDCl₃) δ (ppm): 7.6 (d, 1H, J=7.9 Hz); 6.98 (d, 1H, J=7.9Hz); 6.79 (m, 3H);

2.59 (t, 2H, J=7.6 Hz); 1.67 (se, 2H, J=7.4 Hz); 0.97 (t, 3H, J=7.2 Hz).

b) 2-[(3-amino-6-chloropyridin-2-yl)oxy]-5-propylphenol

To a solution of 6-chloro-2-(2-methoxy-4-propyl phenoxy) pyridin-3-amine(0.1 mmol; 30 mg) under argon, in dichloromethane (2 mL), cooled to −78°C., was added BBr₃ (0.5 mmol; 0.5 mL) dropwise. The reaction mixture wasallowed to stir for 5 hr, with gradual warming to −20° C. At −20° C.,the reaction was hydrolysed with saturated NH₄Cl (4 mL), extracted withdichoromethane (3*10 mL). Combined organic phases dried over Na₂SO₄,concentrated in vacuo, to give the desired product as a light brownsolid without further purification (27 mg; 0.1 mmol; 97%).

¹H NMR (CDCl₃) δ (ppm): 7.06 (d, 1H, J=8.0 Hz); 6.99 (d, 1H, J=8.2 Hz);6.89 (m, 2H); 6.69 (d, 1H, J=8.1 Hz); 2.52 (t, 2H, J=7.7 Hz); 1.64 (se,2H, J=7.5 Hz); 0.93 (t, 3H, J=7.4 Hz).

EXAMPLE 2 2-[(5-amino-6-chloropyridin-2-yl)oxy]-5-propylphenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for2-chloro-6-(2-methoxy-4-propylphenoxy)pyridin-3-amine (0.14 mmol; 40 mg)the title compound (30 mg; 0.11 mmol; 77%). was prepared without anypurification as a light brown solid.

¹H NMR (CDCl₃) δ (ppm): 7.13 (d, 1H, J=8.4 Hz), 6.94 (d, 1H, J=8.2 Hz);6.88 (s, 1H); 6.74 (d, 1H, J=8.4 Hz); 6.66 (d, 1H, J=8.2 Hz); 2.52 (t,2H, J=7.6 Hz), 1.63 (se, 2H, J=7.5 Hz); 0.95 (t, 3H, J=7.3 Hz).

EXAMPLE 3 5-ethyl-2-[(6-fluoropyridin-2-yl)oxy]phenol a)2-(4-ethyl-2-methoxyphenoxy)-6-fluoropyridine

To a suspension of NaH (1.2 mmol; 50 mg) in anhydrous DMSO (1 mL) underargon, was added 4-ethyl-2-methoxyphenol (1 mmol; 152.2 mg) followed by2,6-difluoropyridine (1 mmol; 0.1 ml). The reaction mixture was stirredat 120° C. overnight. After quenching with NaOH (0.1N; 3 mL), themixture was extracted with dichloromethane (3*5 mL). Combined organicphases were dried over Na₂SO₄, concentrated in vacuo, to give the titlecompound as a light yellow oil (250 mg; 1 mmol; 100%), used withoutfurther purification.

MS(ES): m/e 248 (M+H)⁺.

b) 5-ethyl-2-[(6-fluoropyridin-2-yl)oxy]phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for2-(4-ethyl-2-methoxyphenoxy)-6-fluoropyridine (250 mg, 1 mmol) the titlecompound (80 mg, 34%) was prepared as a white solid after purificationby flash chromatography on silica gel (gradientdichloromethane/methanol).

MS(ES): m/e 234 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 7.77 (q, 1H, J1=7.9 Hz, J2=8.0 Hz); 7.01 (d, 1H,J=8.2 Hz); 6.92 (d, 1H, J=1.9 Hz); 6.75 (td, 2H, J1=8.2 Hz, J2=2.0 Hz);6.64 (dd, 1H, J1=7.9 Hz, J2=2.4 Hz); 2.62 (q, 2H, J1=7.6 Hz, J2=7.6 Hz);1.23 (t, 3H, J=7.6 Hz).

Alternatively compound of example 3 can be synthesized starting from2-Benzyloxy-4-ethyl-phenol instead of 4-ethyl-2-methoxyphenol accordingto the following procedure:

c) 4-ethyl-2-hydroxyphenyl-4-methylbenzenesulfonate

a′) To a solution of 2-methoxy-4-ethylphenol (26.3 mmol; 4.0 g), NaI(5.25 mmol; 788 mg), and K₂CO₃ (28.9 mmol; 3.98 g), under argon, inacetonitrile (20 mL) was added tosyl chloride (27.6 mmol; 5.24 g). Thereaction mixture was stirred at 70° C. for 30 hr, then quenched withNaOH (0.1N; 50 mL), and extracted with ethyl acetate (3*20 mL). Combinedorganic phases were washed with saturated NaHCO₃ sat. (50 mL) then water(50 mL), dried over MgSO₄ and concentrated in vacuo. The crude wasrecristallized in cyclohexane (10 mL) to yield a brown oil (5.53 g; 18.1mmol; 68%) engaged without further purification in step b′.

b′) To a solution of 5 g of Toluene-4-sulfonic acid4-ethyl-2-methoxy-phenyl ester (16.3 mmol), under argon, indichloromethane (15 mL), cooled to −78° C., was added BBr₃ (35 mmol; 35mL) dropwise. The reaction mixture was allowed to stir for 6 hr, withgradual warming to −20° C. At −78° C., the reaction was hydrolysed withsaturated NH₄Cl (30 mL), extracted with dichoromethane (2*10 mL).Combined organic phases were washed with 100 mL of saturated NaHCO₃,dried over Na₂SO₄, concentrated in vacuo, the title compound (1.97 g;41%) was obtained as a colourless oil, after purification on silica gel(dichloromethane/cyclohexane: gradient).

¹H NMR (CDCl₃) δ (ppm): 7.76 (d, 2H, J=8.1 Hz); 7.34 (d, 2H, J

-   -   7.9 Hz); 6.84 (s, 1H); 6.65 (d, 1H, J=8.4 Hz); 6.58 (d, 1H,        J=6.8 Hz); 5.86 (s1, 1H); 2.56 (q, 2H, J=7.6 Hz); 2.46 (s, 3H);        1.18 (t, 3H, J=7.6 Hz).

d) 2-(benzyloxy)-4-ethylphenyl-4-methylbenzenesulfonate

To a solution of 4-ethyl-2-hydroxyphenyl-4-methylbenzenesulfonate (5mmol; 1.46 g) under argon, in acetone (10 mL), were added K₂CO₃ (6 mmol;0.83 g), NaI (1 mmol; 0.15 g), and benzylbromide (5.5 mmol; 0.65 mL).The reaction was stirred at 40° C. for 5 hr. The reaction mixture wasconcentrated then hydrolysed with NH₄Cl sat. (10 mL) and extracted withethyl acetate (3*5 mL). Combined organic phases were washed withsaturated NaHCO₃ (10 mL), dried over Na₂SO₄, concentrated. The residuewas purified on silica gel (dichloromethane/cyclohexane: gradient) toyield the title compound as a clear oil (1.68 g; 4.39 mmol; 87%).

¹H NMR (CDCl₃) δ (ppm): 7.69 (d, 2H, J=8.3 Hz); 7.34 (m, 5H); 7.11 (m,3H); 6.74 (m, 2H); 4.87 (s, 2H); 2.59 (q, 2H, J=7.6 Hz); 2.37 (s, 3H);1.19 (t, 3H, J=7.6 Hz).

e) 2-Benzyloxy-4-ethyl-phenol

To a solution of 2-(benzyloxy)-4-ethylphenyl-4-methylbenzenesulfonatemethylbenzenesulfonate (0.26 mmol; 100 mg) under argon, in methanol (2mL), was added magnesium (2.61 mmol; 0.63 g). The reaction was stirredat room temperature overnight. The reaction mixture was hydrolysed withHCl 1N (3 mL) and extracted with ethyl acetate (3*5 mL). Combinedorganic phases were washed with saturated NaHCO₃ (10 mL), dried over

Na₂SO₄, concentrated. The residue was purified with preparative TLC(dichloromethane/cyclohexane: 9/1) to yield the title compound as ayellow oil (48 mg; 0.21 mmol; 80%).

MS (ES) m/e 229 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 7.43 (m, 5H); 6.90 (d, 1H, J=8.0 Hz); 6.82 (s,1H); 6.75 (d, 1H, J=8.0 Hz); 5.55 (s, 1H); 5.12 (s, 2H); 2.61 (q, 2H,J=7.6 Hz); 1.25 (t, 3H, J=7.6 Hz).

f) 2-[2-(benzyloxy)-4-ethylphenoxy]-6-fluoropyridine

To a suspension of K₂CO₃ (0.25 mmol; 35 mg) in anhydrous acetonitrile (2mL) under argon, was added 2-Benzyloxy-4-ethyl-phenol (48 mg; 0.21 mmol)followed by 2,6-difluoropyridine (100 μL; 1.10 mmol). The reactionmixture was stirred at 80° C. overnight.

Concentrated under argon, washed with NH₄Cl (0.1N; 3 mL), the mixturewas extracted with ethyl acetate (3*3 mL). Combined organic phases werewashed with NaHCO₃ dried over MgSO₄, concentrated in vacuo, to give thetitle product as a light oil (28.5 mg; 42%), after purification bypreparative TLC (cyclohexane/ethyl acetate: 9/1).

¹H NMR (CDCl₃) δ (ppm): 7.70 (q, 1H, J=8.0 Hz); 7.27 (m, 3H); 7.17 (d,2H, J=5.8 Hz); 7.11 (d, 1H, J=8.0 Hz); 6.90 (s, 1H); 6.86 (d, 1H, J=8.1Hz); 6.73 (d, 1H, J=7.5 Hz); 6.56 (dd, 1H, J, =7.8 Hz, J₂=2.4 Hz); 5.06(s, 2H); 2.66 (q, 2H, J=7.6 Hz); 1.27 (t, 3H, J=7.6 Hz).

g) 5-ethyl-2-[(6-fluoropyridin-2-yl)oxy]phenol

2-[2-(benzyloxy)-4-ethylphenoxy]-6-fluoropyridine (28 mg; 0.09 mmol) wasdissolved in ethanol (4 mL), under argon. Palladium on charcoal (4 mg;0.02 mmol) was added and the reaction was flushed twice with hydrogen,then left to stir overnight at room temperature. The reaction mixturewas filtered on celite, then rinsed with methanol (3*3 mL).Concentration yielded a white solid (25 mg; 98%) of title compound.

MS (ES) m/e 234 (M+H)⁺.

EXAMPLE 42-[(6-fluoropyridin-2-yl)oxy]-5-{2-[(6-fluoropyridin-2-yl)oxy]ethyl}phenola)2-fluoro-6-(4-{2-[(6-fluoropyridin-2-yl)oxy]ethyl}-2-methoxyphenoxy)pyridine

To a suspension of KOH (2 mmol; 112 mg) in anhydrous DMF (1 mL) underargon, was added 4-(2-hydroxyethyl)-2-methoxyphenol (1 mmol; 168 mg)followed by 2,6-Difluoropyridine (1 mmol; 0.1 ml). The reaction mixturewas stirred at 110° C. for 20 h.

After quenching with NaOH (0.1N; 3 mL), the mixture was extracted withethyl acetate (3*5 mL). Combined organic phases were dried over Na₂SO₄,concentrated in vacuo, to give a clear oil (50 mg; 0.14 mmol; 28%),after purification by flash chromatography on silica gel (gradientcylohexane/dichloromethane). MS(ES): m/e 359 (M+H)⁺

b)2-[(6-fluoropyridin-2-yl)oxy]-5-{2-[(6-fluoropyridin-2-yl)oxy]ethyl}phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for2-fluoro-6-(4-{12-[(6-fluoropyridin-2-yl)oxy]ethyl}-2-methoxyphenoxy)pyridine(50 mg, 0.14 mmol) the title compound (20 mg, 30%) was prepared as awhite solid after purification by preparative TLC(dichloromethane/methanol—9/1).

MS(ES): m/e 234 (M+H)⁺.

¹H NMR (CDCl₃) b (ppm): 7.76 (q, 1H, J1=7.9 Hz, J2=8.0 Hz); 7.62 (q, 1H,J1=8.3 Hz, J2=7.99); 7.02 (m, 2H); 6.83 (dd, 1H, J1=8.2 Hz, J2=2.0 Hz);6.76 (d, 1H, J1=7.8 Hz); 6.65 (dd, 1H, J1=7.7 Hz, J2=1.8 Hz); 6.59 (dd,1H, J1=8.0 Hz, J2=1.1 Hz); 6.45 (dd, 1H, J1=7.7 Hz, J2=2.1 Hz); 6.09 (s,1H); 4.47 (t, 2H, J=6.9 Hz); 3.03 (t, 2H, J=6.9 Hz).

EXAMPLE 5 2-[(6-fluoropyridin-2-yl)oxy]-5-propylphenol a)2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine

According to the procedure of example 4 (a) except substituting4-(2-hydroxyethyl)-2-methoxyphenol for 2-methoxy-4-propylphenol (2.1mmol; 0.34 mL) the title compound (449 mg; 86%) was prepared as a whitesolid, after purification by silica gel chromatography (gradientcyclohexane/dichloromethane).

MS (ES) m/e 262 (M+H)⁺

b) 2-[(6-fluoropyridin-2-yl)oxy]-5-propylphenol

To a solution of 2-fluoro-6-(2-methoxy-4-propylphenoxy) pyridine (1.7mmol; 449 mg) under argon, in dichloromethane (1.5 mL), cooled to −78°C., was added BBr₃ (17 mmol; 1M in CH₂Cl₂; 17 mL). The reaction mixturewas allowed to stir overnight, with gradual heating to room temperature.At −20° C., the reaction was hydrolysed with saturated NH₄Cl (3 mL),extracted with ethyl acetate (3*10 mL). Combined organic phases weredried over MgSO₄, concentrated in vacuo. The residue was chromatographedon silica gel (gradient cyclohexane/dichloromethane) to give the desiredproduct as a white solid (160 mg; 0.65 mmol; 38%).

MS (ES) m/e 248 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 7.78 (q, 1H, J=8 Hz); 7.02 (d, 1H, J=8.4 Hz);6.92 (d, 1H, J=2 Hz); 6.76 (ta, 2H, J=9.2 Hz); 6.65 (dd, 1H, J₁=8 Hz,J₂=2.4 Hz); 2.58 (t, 2H, J=7.6 Hz); 1.67 (s, 2H, J=7.6 Hz); 0.98 (t, 3H,J=7.2 Hz).

Alternatively compound of example 5 can be synthesized starting from the2-(benzyloxy)-4-propylphenol instead of -methoxy-4-propylphenol usingthe same protocol as example 3 step f) and g).

Synthesis of 2-(benzyloxy)-4-propylphenol a) 2-methoxy-4-propylphenyl4-methylbenzenesulfonate

To a solution of 2-methoxy-4-propylphenol (10.0 mmol; 1.6 mL), NaI (1.0mmol; 150 mg), and K₂CO₃ (11.0 mmol; 1.52 g), under argon, inacetonitrile (20 mL) was added tosyl chloride (10.5 mmol; 2.0 g). Thereaction mixture was stirred at 70° C. for 36 hr, then quenched withNaOH (0.1N; 3 mL), and extracted with ethyl acetate (2*10 mL). Combinedorganic phases were washed with saturated NaHCO₃ sat. (5 mL), dried overMgSO₄, concentrated in vacuo. The crude was chromatographed on silicagel (gradient cyclohexane/dichloromethane) to yield the desired compoundas a clear oil (2.13 g; 6.6 mmol; 66%).

MS (ES) m/e 321 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 7.77 (d, 2H, J=8.2 Hz); 7.31 (d, 2H, J=8.0 Hz);7.03 (d, 1H, J=8.2 Hz); 6.70 (m, 2H); 3.57 (s, 3H); 2.54 (t, 2H, J=7.7Hz); 2.46 (s, 3H); 1.63 (se, 2H, J=7.6 Hz); 0.95 (t, 3H, J=7.3 Hz).

b) 2-hydroxy-4-propylphenyl 4-methylbenzenesulfonate

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for2-methoxy-4-propylphenyl 4-methylbenzenesulfonate (64 mg, 0.2 mmol), thetitle compound (40 mg; 65%) was prepared as a clear oil, afterpurification by silica gel chromatography (gradientcyclohexane/dichloromethane).

MS (ES) m/e 305 (M−H)⁻

NMR¹H (CDCl₃) δ (ppm): 7.80 (d, 2H, J=8.3 Hz); 7.37 (d, 2H, J=8.1 Hz);6.85 (s, 1H); 6.71 (d, 1H, J=8.3 Hz); 6.60 (d, 1H, J=8.3 Hz); 6.11 (s,1H); 2.53 (t, 2H, J=7.6 Hz); 2.50 (s, 3H); 1.63 (se, 2H, J=7.5 Hz); 0.95(t, 3H, J=7.3 Hz).

c) 2-(benzyloxy)-4-propylphenyl 4-methylbenzenesulfonate

To a solution of 2-hydroxy-4-propylphenyl 4-methylbenzenesulfonate (0.11mmol; 33 mg) under argon, in acetone (0.2 mL), were added K₂CO₃ (0.13mmol; 18 mg), NaI (0.02 mmol; 3 mg), and benzylbromide (0.12 mmol; 0.015mL). The reaction was stirred at 40° C. for 5 hr. The reaction mixturewas then hydrolysed with NH₄Cl sat. (3 mL) and extracted with ethylacetate (3*5 mL). Combined organic phases were washed with saturatedNaHCO₃ (3 mL), dried over MgSO₄, concentrated. The residue was purifiedby preparative TLC (dichloromethane) to yield the title compound as aclear oil (28 mg; 0.07 mmol; 64%).

MS (ES) m/e 397 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 7.71 (d, 2H, J=8.1 Hz); 7.34 (m, 5H); 7.12 (d,3H, J=8.3 Hz); 6.74 (s, 2H); 4.88 (s, 2H); 2.54 (t, 2H, J=7.6 Hz); 2.39(s, 3H); 1.61 (se, 2H, J=7.4 Hz); 0.92 (t, 3H, J=7.3 Hz).

d) 2-(benzyloxy)-4-propylphenol

To a solution of 2-(benzyloxy)-4-propylphenyl 4-methylbenzenesulfonate(0.07 mmol; 28 mg) under argon, in a mixture of ethanol (0.2 mL) andwater (0.1 mL), was added KOH (0.09 mmol; 5 mg). The reaction wasrefluxed for 1 hr, then hydrolysed with NH₄Cl sat. (3 mL), and extractedwith ethyl acetate (3*5 mL). Combined organic phases were washed withsaturated NaHCO₃ (3 mL), dried over MgSO₄, concentrated. The residue waspurified by preparative TLC (cyclohexane/dichloromethane) to yield thetitle compound as a clear oil (16 mg; 0.06 mmol; 86%).

MS (ES) m/e 243 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 7.41 (m, 5H); 6.87 (d, 1H, J=8.0 Hz); 6.79 (s,1H); 6.71 (d, 1H, J=8.0 Hz); 5.51 (s, 1H); 5.11 (s, 2H); 2.53 (t, 2H,J=7.6 Hz); 1.61 (se, 2H, J=7.5 Hz); 0.94 (t, 3H, J=7.3 Hz).

EXAMPLE 6 2-[(6-chloropyridin-2-yl)oxy]-5-propylphenol a)2-chloro-6-(2-methoxy-4-propylphenoxy)pyridine

According to the procedure of example 5 (a) except substituting2,6-difluoropyridine for 2,6-dichlororopyridine (296 mg, 2 mmol), thetitle compound (450 mg; 81%) was prepared as a clear oil, afterpurification by silica gel chromatography (gradient cyclohexane/ethylacetate).

MS (ES) m/e 278 (M+H)⁺

b) 2-[(6-chloropyridin-2-yl)oxy]-5-propylphenol

According to the procedure of example 5 (b), except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for2-chloro-6-(2-methoxy-4-propylphenoxy)pyridine (450 mg, 1.62 mmol), thetitle compound (148 mg; 35%) was prepared as white solid afterpurification by silica gel chromatography (gradient cyclohexane/ethylacetate).

MS (ES) m/e 264 (M+H)⁺

NMR¹H (CD₃OD) δ (ppm): 7.70 (t, 1H, J=8.0 Hz); 7.06 (d, 1H, J=7.7 Hz);6.93 (d, 1H, J=8.1 Hz); 6.78 (s, 1H); 6.69 (m, 2H); 2.53 (t, 2H, J=7.8Hz); 1.65 (se, 2H, J=7.6 Hz); 0.95 (t, 3H, J=7.4 Hz).

EXAMPLE 7 2-[(6-aminopyridin-2-yl)oxy]-5-propylphenol a)6-(2-methoxy-4-propylphenoxy) pyridin-2-amine

According to the procedure of example 5(a) except substituting2,6-difluoropyridine for 2-amino-6-bromopyridine (173 mg, 1 mmol) thetitle compound (125 mg; 48%) was prepared as a clear oil, afterpurification by silica gel chromatography (gradientcyclohexane/dichloromethane).

MS (ES) m/e 259 (M+H)⁺

b) 2-[(6-aminopyridin-2-yl)oxy]-5-propylphenol

According to the procedure of example 5(b) except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for6-(2-methoxy-4-propylphenoxy)pyridin-2-amine (125 mg, 0.48 mmol), thetitle compound (5 mg; 4%) was prepared as a clear oil, after preparativeTLC (cyclohexane/dichloromethane).

MS (ES) m/e 245 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 7.45 (t, 1H, J=7.9 Hz); 7.02 (d, 1H, J=8.1 Hz);6.90 (s, 1H); 6.70 (d, 1H, J=8.0 Hz); 6.27 (d, 1H, J=7.8 Hz); 6.22 (d,1H, J=7.9 Hz); 4.45 (br, 2H); 2.55 (t, 2H, J=7.6 Hz); 1.66 (se, 2H,J=7.6 Hz); 0.97 (t, 3H, J=7.3 Hz).

EXAMPLE 8 4-[(6-fluoropyridin-2-yl)oxy]-3-hydroxy benzaldehyde a)4-[(6-fluoropyridin-2-yl)oxy]-3-methoxybenzaldehyde

According to the procedure of example 4 (a), except substituting4-(2-hydroxyethyl)-2-methoxyphenol for 4-hydroxy-3-methoxybenzaldehyde(304 mg, 2 mmol) the title compound (220 mg; 44%) was prepared as awhite solid, after purification by silica gel chromatography (gradientcyclohexane/ethyl acetate).

MS (ES) m/e 248 (M+H)⁺

b) 4-[(6-fluoropyridin-2-yl)oxy]-3-hydroxybenzaldehyde

According to the procedure of example 5 (b) except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for4-[(6-fluoropyridin-2-yl)oxy]-3-methoxybenzaldehyde (220 mg, 0.89 mmol),the title compound (10 mg; 7%) was prepared as a white solid, afterpurification by preparative TLC (cyclohexane/ethyl acetate).

MS (ES) m/e 234 (M+H)⁺

NMR¹H (CD₃OD) δ (ppm): 9.95 (s, 1H); 7.88 (q, 1H, J₁=8.0 Hz); 7.59 (d,1H, J=2.0 Hz); 7.49 (dd, 1H, J₁=8.4 Hz, J₂=2.0 Hz); 7.29 (da, 2H, J=8.0Hz); 6.93 (d, 1H, J=7.6 Hz); 6.75 (dd, 1H, J₁=8.0 Hz, J₂=2.0 Hz).

EXAMPLE 9 2-[(6-fluoropyridin-2-yl)oxy]-5-methylphenol a)2-fluoro-6-(2-methoxy-4-methylphenoxy)pyridine

According to the procedure of example 4 (a), except substituting4-(2-hydroxyethyl)-2-methoxyphenol for 2-methoxy-4-methylphenol (0.25mL, 2 mmol) the title compound (457 mg; 97%) was prepared as a whitesolid, after purification by silica gel chromatography (gradientcyclohexane/dichloromethane).

MS (ES) m/e 234 (M+H)⁺

b) 2-[(6-fluoropyridin-2-yl)oxy]-5-methylphenol

According to the procedure of example 5 (b) except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for2-fluoro-6-(2-methoxy-4-methylphenoxy)pyridine (457 mg, 1.93 mmol), thetitle compound (71 mg; 16%) was prepared as a white solid, after washingwith diethyl ether.

MS (ES) m/e 220 (M+H)⁺

NMR¹H (CD₃OD) δ (ppm): 7.81 (q, 1H, J₁=8.0 Hz); 6.79 (m, 2H); 6.63 (m,3H); 2.28 (s, 3H).

EXAMPLE 10 4-[(6-fluoropyridin-2-yl)oxy]-4′-methylbiphenyl-3-ol a)2-(4-chloro-2-methoxyphenoxy)-6-fluoropyridine

According to the procedure of example 4 (a) except substituting4-(2-hydroxyethyl)-2-methoxyphenol for 2-methoxy-4-chlorophenol (0.24mL, 2 mmol) the title compound (423 mg; 84%) was prepared as a whitesolid, after purification by silica gel chromatography (gradientcyclohexane/dichloromethane).

MS (ES) m/e 254 (M+H)⁺

b) 2-fluoro-6-[(3-methoxy-4′-methylbiphenyl-4-yl)oxy]pyridine

To a solution of 2-(4-chloro-2-methoxyphenoxy)-6-fluoropyridine (0.53mmol; 135 mg) and 4-methylphenylboronic acid (0.94 mmol; 127 mg) in adegased DME/water mixture (1.5/0.5 mL), under argon were added K₂CO₃(2.0 mmol; 276 mg), then tetrakis(triphenylphosphine)palladium (0.07mmol; 47 mg). The reaction was stirred at 105° C. for 48 hr. Afterconcentration, the residue was purified by flash chromatography(gradient cyclohexane/dichloromethane) to yield the desired productalong with remaining starting material (160 mg; 0.53 mmol; 100% max).

MS (ES) m/e 310 (M+H)⁺

c) 4-[(6-fluoropyridin-2-yl)oxy]-4′-methylbiphenyl-3-ol

According to the procedure of example 5 (b) except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for2-fluoro-6-[(3-methoxy-4′-methyl-1,1′-biphenyl-4-yl)oxy]pyridine (160mg, 0.53 mmol), the title compound (37 mg; 24%) was prepared as a whitesolid, after purification by preparative TLC (dichloromethane).

MS (ES) m/e 296 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 7.81 (q, 1H, J=8.0 Hz); 7.50 (d, 2H, J=8.1 Hz);7.32 (d, 1H, J=1.6 Hz); 7.27 (d, 2H, J=8.0 Hz); 7.17 (m, 2H); 6.84 (d,1H, J=8.0 Hz); 6.68 (dd, 1H, J₁=7.9 Hz, J₂=2.2 Hz); 6.33 (sb, 1H); 2.42(s, 3H).

EXAMPLE 11 2-{[5-(4-bromobut-1-yn-1-yl)pyridin-2-yl]oxy}-5-propylphenola) 4-[6-(2-methoxy-4-propylphenoxy)pyridin-3-yl]but-3-yn-1-ol

To a solution of 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine (0.19mmol; 60 mg) under argon, in degased DME (1 mL) were added 3-butyn-1-ol(0.47 mmol; 33 mg), Pd/C (0.02 mmol; 42 mg), CuI (0.04 mmol; 7.6 mg),K₂CO₃ (0.47 mmol; 64 mg), and triphenylphosphine (0.08 mmol; 21 mg). Thereaction mixture was stirred at 80° C. overnight, then filtered oncelite, washed with ether (3 mL) then ethyl acetate (3 mL). Combinedorganic phases were washed with saturated NH₄Cl (3 mL), dried overMgSO₄, concentrated. The residue was purified by preparative TLC(dichloromethane/ethyl acetate) to yield the desired compound as a clearoil (25 mg; 0.08 mmol; 42%).

MS (ES) m/e 312 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 8.21 (d, 1H, J=1.8 Hz); 7.67 (dd, 1H, J₁=8.6 Hz,J₂=2.3 Hz); 7.04 (d, 1H, J=7.9 Hz); 6.82 (m, 3H); 3.81 (t, 2H, J=6.3Hz); 3.75 (s, 3H); 2.68 (t, 2H, J 6.3 Hz); 2.60 (t, 2H, J=7.8 Hz); 2.07(sb, 1H); 1.69 (se, 2H, J=7.6 Hz); 0.98 (t, 3H, J=7.4 Hz).

b) 2-{[5-(4-bromobut-1-yn-1-yl)pyridin-2-yl]oxy}-5-propylphenol

According to the procedure of example 5 (b) except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for4-[6-(2-methoxy-4-propylphenoxy)pyridin-3-yl]but-3-yn-1-ol (25 mg, 0.08mmol), the title compound (6 mg; 21%) was prepared as a clear oil, afterpurification by preparative TLC (dichloromethane).

MS (ES) m/e 361 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 8.24 (s, 1H); 7.75 (d, 1H, J=8.5 Hz); 7.01 (d,1H, J=8.2 Hz); 6.93 (m, 2H); 6.74 (d, 1H, J=8.1 Hz); 3.54 (t, 2H, J=7.2Hz); 2.99 (t, 2H, J=7.2 Hz); 2.56 (t, 2H, J=7.8 Hz); 1.66 (se, 2H, J=7.6Hz); 0.96 (t, 3H, J=7.4 Hz).

EXAMPLE 122-{[5-(4-hydroxybut-1-yn-1-yl)pyridin-2-yl]oxy}-5-propylphenol

The title compound (1 mg; 4%) was isolated from the example 11 (b) as awhite solid, after purification by preparative TLC (dichloromethane).

MS (ES) m/e 298 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 8.25 (s, 1H); 7.75 (d, 1H, J=8.4 Hz); 7.02 (d,1H, J=8.5 Hz); 6.93 (m, 2H); 6.74 (d, 1H, J=8.0 Hz); 3.84 (t, 2H, J=6.2Hz); 2.71 (t, 2H, J=6.2 Hz); 2.56 (t, 2H, J=7.9 Hz); 1.66 (se, 2H, J=7.6Hz); 0.96 (t, 3H, J=7.4 Hz).

EXAMPLE 13 2-[(6-fluoropyridin-2-yl)oxy]-5-isobutylphenol a)2-(4-bromo-2-methoxyphenoxy)-6-fluoropyridine

According to the procedure of example 4 (a) except substituting4-(2-hydroxyethyl)-2-methoxyphenol for 2-methoxy-4-bromophenol (406 mg,2 mmol) the title compound (540 mg; 90%) was prepared as a clear oil,after purification by silica gel chromatography (gradientcyclohexane/dichloromethane).

MS (ES) m/e 299 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 7.79 (q, 1H, J=8.0 Hz); 7.16 (m, 2H); 7.06 (d,1H, J=9.0 Hz); 6.80 (d, 1H, J=8.0 Hz); 6.62 (d, 1H, J=7.8 Hz); 3.81 (s,3H).

b) 2-fluoro-6-(4-isobutyl-2-methoxyphenoxy)pyridine

To a suspension of Pd(PPh₃)₄ (0.025 mmol; 17 mg) under argon, inanhydrous, degased dioxane (2 mL), sheltered from light, were added2-(4-bromo-2-methoxyphenoxy)-6-fluoropyridine (0.51 mmol; 151 mg), thenisobutyl zinc bromide (1.0 mmol; 2.0 mL). The reaction was heated to105° C. for 24 hr. The mixture was then hydrolysed with water (3 mL),extracted with ethyl acetate (3*3 mL). Combined organic phases weredried over MgSO₄, concentrated under reduced pressure. The crude wasthen purified by preparative chromatography(cyclohexane/dichloromethane) to yield the desired product as a clearoil (28 mg; 0.10 mmol; 20%).

MS (ES) m/e 276 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 7.71 (q, 1H, J=8.0 Hz); 7.04 (d, 1H, J=7.9 Hz);6.78 (m, 2H); 6.68 (d, 1H, J=7.3 Hz); 6.56 (d, 1H, J=7.8 Hz); 3.77 (s,3H); 2.50 (d, 2H, J=7.2 Hz); 1.90 (se, 1H, J=6.7 Hz); 0.96 (d, 6H, J=6.6Hz).

c) 2-[(6-fluoropyridin-2-yl)oxy]-5-isobutylphenol

According to the procedure of example 5 (b) except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for2-fluoro-6-(4-isobutyl-2-methoxyphenoxy)pyridine (25 mg, 0.1 mmol), thetitle compound (18 mg; 69%) was prepared as a clear oil, withoutpurification.

MS (ES) m/e 262 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 7.78 (q, 1H, J=8.0 Hz); 7.02 (d, 1H, J=8.2 Hz);6.89 (s, 1H); 6.77 (d, 1H, J=8.0 Hz); 6.72 (d, 1H, J=8.2 Hz); 6.66 (d,1H, J=7.9 Hz); 2.46 (d, 2H, J=7.2 Hz); 1.88 (se, 1H, J=6.7 Hz); 0.94 (d,6H, J=6.6 Hz).

EXAMPLE 14 2-[(6-fluoropyridin-2-yl)oxy]-5-(hydroxymethyl) phenol a){4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}methanol

According to the procedure of example 4 (a) except substituting4-(2-hydroxyethyl)-2-methoxyphenol for 4-(hydroxymethyl)-2-methoxyphenol(308 mg; 2 mmol) the title compound (200 mg; 40%) was prepared as aclear oil, after purification by silica gel chromatography (gradientcyclohexane/ethyl acetate).

MS (ES) m/e 250 (M+H)⁺

b) 2-[(6-fluoropyridin-2-yl)oxy]-5-(hydroxymethyl)phenol

According to the procedure of example 5 (b) except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}methanol (104 mg, 0.42mmol), the title compound (98 mg; 98%) was prepared as a white solid,after washing with diethyl ether.

MS (ES) m/e 236 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 7.81 (q, 1H, J=8.0 Hz); 7.11 (s, 1H); 7.08 (d,1H, J=8.3 Hz); 6.95 (d, 1H, J=8.3 Hz); 6.83 (d, 1H, J=7.9 Hz); 6.68 (d,1H, J=7.9 Hz); 4.46 (s, 2H).

EXAMPLE 15 4-[(6-fluoropyridin-2-yl)oxy]-3-hydroxybenzyl acetate

To a solution of 2-[(6-fluoropyridin-2-yl)oxy]-5-(hydroxymethyl)phenol(0.42 mmol; 104 mg) under argon, in anhydrous DMF (0.8 mL), were addedK₂CO₃ (0.5 mmol; 68 mg), DMAP (0.08 mmol; 12 mg), and acetic anhydride(0.41 mmol; 0.04 mL). The reaction was stirred at room temperatureovernight. After dilution with ethyl acetate (4 mL), the organic phasewas washed with saturated NaHCO₃ (3*3 mL), dried (MgSO₄), concentratedin vacuo, purified by preparative TLC (dichloromethane) to yield thetitle compound as a clear oil (3 mg; 0.01 mmol; 3%).

MS (ES) m/e 278 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 7.82 (q, 1H, J=8.0 Hz); 7.56 (m, 3H); 6.82 (d,1H, J=6.9 Hz); 6.68 (dd, 1H, J₁=7.8 Hz, J₂=2.6 Hz); 5.16 (s, 2H); 2.17(s, 3H).

EXAMPLE 16 2-(4-methoxyphenoxy)-5-propylphenol a)2-methoxy-1-(4-methoxyphenoxy)-4-propylbenzene

A mixture containing 2-methoxy-4-propylphenol (0.625 mmol; 100 μl),copper(II) acetate (0.625 mmol; 114 mg), 4-methoxyphenylboronic acid(1.25 mmol; 190 mg), triethylamine (3.12 mmol; 0.43 ml), some crushedmolecular sieves 4 Å in dichloromethane (3 ml) was stirred at rt underair for 24 h. The residue is filtered with chloroform on Celite. Theorganic phase is washed with saturated NH₄Cl, saturated NaHCO₃ andbrine. After drying (MgSO₄), concentration and purification bypreparative TLC on silica gel (ethyl acetate/cyclohexane—20/80), thetitle compound is collected as a colorless oil (70 mg; 0.26 mmol; 41%).

MS (ES) 273 [M+1]⁺ and 295 [M+Na]⁺

NMR¹H (CDCl₃) δ (ppm): 6.94 (d, 2H, J=9.1 Hz); 6.85 (d, 2H, J=9.1 Hz);6.82 (s, 1H); 6.80 (d, 1H, J=8.1 Hz); 6.70 (d, 1H, J=8.2 Hz); 3.87 (s,3H); 3.80 (s, 3H); 2.58 (t, 2H, J=7.7 Hz); 1.67 (se, 2H, J=7.6 Hz); 0.98(t, 3H, J=7.3 Hz).

b) 2-(4-methoxyphenoxy)-5-propylphenol

According to the procedure of example 5 (b) except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for2-methoxy-1-(4-methoxyphenoxy)-4-propylbenzene (0.18 mmol; 50 mg) andadding 4 equivalents (0.735 mmol; 735 μl) of boron tribromide, the titlecompound was prepared in 32% yield (0.06 mmol; 15 mg) after purificationby preparative TLC on silica gel (ethyl acetate/cyclohexane—20/80).

MS (ES) 257 [M−1]⁻

NMR¹H (CDCl₃) δ (ppm): 6.99 (d, 2H, J=9.0 Hz); 6.89 (d, 2H, J=9.0 Hz);6.87 (s, 1H); 6.72 (d, 1H, J=8.2 Hz); 6.63 (d, 1H, J=8.1 Hz); 5.57 (sbr, 1H); 3.82 (s, 3H); 2.54 (t, 2H, J=7.8 Hz); 1.64 (se, 2H, J=7.5 Hz);0.96 (t, 3H, J 7.3 Hz). NOE observed between δ 3.82 and 6.89 ppm.

EXAMPLE 17 N-[3-(2-hydroxy-4-propylphenoxy)phenyl]acetamide a)N-[3-(2-methoxy-4 propylphenoxy)phenyl]acetamide

According to the procedure of example 16 (a) except substituting4-methoxyphenylboronic acid for 3-acetamidophenylboronic acid (1.25mmol; 224 mg) the title compound was prepared in 10% yield (0.06 mmol;18 mg) after purification by preparative TLC on silica gel (ethylacetate/cyclohexane—70/30).

NMR¹H (CDCl₃) δ (ppm): 7.28-7.16 (m, 3H); 7.05 (s, 1H); 6.92 (d, 1H,J=8.0 Hz); 6.83 (s, 1H); 6.76 (d, 1H, J=7.9 Hz); 6.68 (d, 1H, J=7.4 Hz);3.82 (s, 3H); 2.60 (t, 2H, J=7.4 Hz); 2.15 (s, 3H); 1.68 (t, 3H, J=7.4Hz).

b) N-[3-(2-hydroxy-4-propylphenoxy)phenyl]acetamide

According to the procedure of example 5 (b) except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine forN-[3-(2-methoxy-4-propylphenoxy)phenyl]acetamide (0.06 mmol; 17 mg), thetitle compound was prepared in 56% yield (0.03 mmol; 9 mg) afterpurification by preparative TLC on silica gel (ethylacetate/cyclohexane—70/30).

MS (ES) 286 [M+1]⁺ and 308 [M+Na]⁺

NMR¹H (DMSO) δ (ppm): 9.90 (s, 1H); 9.37 (s, 1H); 7.28-7.19 (m, 3H);6.86 (d, 1H, J=8.1 Hz); 6.79 (s, 1H); 6.64 (d, 1H, J=8.1 Hz); 6.52 (d,1H, J=7.9 Hz); 2.00 (s, 3H); 1.59 (se, 2H, J=7.5 Hz); 0.92 (t, 3H, J=7.3Hz).

EXAMPLE 18 2-{[6-(butylamino)pyridin-2-yl]oxy}-5-ethylphenol a)N-butyl-6-(4-ethyl-2-methoxyphenoxy)pyridin-2-amine

To 2-(4-ethyl-2-methoxyphenoxy)-6-fluoropyridine (94 mg; 0.32 mmol),under argon, was added butylamine (0.5 mL). The reaction was heated to80° C. for 18 hours. The mixture was concentrated in vacuo. Afterquenching with saturated NaHCO₃ (10 mL), extractions withdichloromethane (3*5 mL), the organic phase was dried over NaSO₄, andconcentrated in vacuo to give the title compound as a light brown oilused without further purification (87 mg; 0.29 mmol; 89%).

MS (ES) m/e 301 (M+H)⁺

b) 2-{[6-(butylamino)pyridin-2-yl]oxy}-5-ethylphenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine forN-butyl-6-(4-ethyl-2-methoxyphenoxy)pyridin-2-amine (87 mg; 0.29 mmol),the title compound (36 mg; 43%) was obtained as a light brown oil, afterpurification by preparative TLC (cyclohexane/ethyl acetate: 8/2)

MS (ES) m/e 287 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 7.41 (t, 1H, J=7.9 Hz); 7.01 (d, 1H, J=8.1 Hz);6.91 (s, 1H); 6.69 (d, 1H, J=8.0 Hz); 6.17 (d, 1H, J=7.8 Hz); 6.06 (d,1H, J=8.1 Hz); 4.56 (s1.1H); 3.18 (t, 2H, J=7.0 Hz); 2.61 (q, 2H, J=7.5Hz); 1.55 (qt, 2H, J=7.5 Hz); 1.39 (se, 2H, J=7.4 Hz); 1.23 (t, 3H,J=7.6 Hz); 0.93 (t, 3H, J=7.3 Hz).

EXAMPLE 19 2-[(6-ethoxypyridin-2-yl)oxy]-5-ethylphenol a)2-ethoxy-6-(4-ethyl-2-methoxyphenoxy)pyridine

To a solution of sodium (55 mg; 2.39 mmol), under argon, in ethanol (2mL), was added 2-(4-ethyl-2-methoxyphenoxy)-6-fluoropyridine (82 mg;0.33 mmol). The reaction was heated to 80° C. for 16 hours then to 90°C. for 26 hours. The mixture was concentrated in vacuo. After quenchingwith saturated NaHCO₃ (10 mL), extractions with ethyl acetate (3*5 mL),the organic phase was dried over NaSO₄, and concentrated in vacuo togive the desired product as a light brown oil used without furtherpurification (82 mg; 0.30 mmol; 90%).

MS (ES) m/e 274 (M+H)⁺

b) 2-[(6-ethoxypyridin-2-yl)oxy]-5-ethylphenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for2-ethoxy-6-(4-ethyl-2-methoxyphenoxy)pyridine (82 mg; 0.30 mmol), thetitle compound (31 mg; 37%) was prepared as a light brown oil, afterpurification by preparative TLC (cyclohexane/ethyl acetate: 8/2).

MS (ES) m/e 260 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 7.56 (t, 1H, J=7.6 Hz); 7.01 (d, 1H, J=8.2 Hz);6.91 (d, 1H, J=1.8 Hz); 6.70 (dd, 1H, J₁=1.9 Hz, J₂=8.2 Hz); 6.46 (d,1H, J=5.1 Hz); 6.43 (d, 1H, J=4.8 Hz); 4.22 (q, 2H, J=7.0 Hz); 2.61 (q,2H, J=7.6 Hz); 1.33 (t, 3H, J=7.1 Hz); 1.23 (t, 3H, J=7.0 Hz).

EXAMPLE 20 2-[4-amino-2-(trifluoromethyl)phenoxy]-5-ethyl phenol a)4-ethyl-2-methoxy-1-[4-nitro-2(trifluoromethyl)phenoxy]benzene

To a suspension of K₂CO₃ (2 mmol; 276 mg) in anhydrous acetonitrile (1mL) under argon, was added 2-methoxy-4-ethylphenol (0.285 mL; 2 mmol)followed by 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (418 mg; 2mmol). The reaction mixture was stirred at 80° C. overnight.Concentrated under argon, washed with NaOH (0.1N; 3 mL), the mixture wasextracted with ethyl acetate (2*3 mL). Combined organic phases weredried over MgSO₄, concentrated in vacuo, to give the title product as alight brown oil (651 mg; 95%), used without further purification.

MS (ES) m/e 342 (M+H)⁺.

b) 4-(4-ethyl-2-methoxyphenoxy)-3-(trifluoromethyl)aniline

4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene (1.90mmol; 651 mg) was dissolved in anhydrous THF (8 mL) under argon.Palladium on charcoal (0.095 mmol; 20 mg) was added and the reaction wasflushed twice with hydrogen, then left to stir overnight. The reactionmixture was filtered on celite, rinsed with methanol (3*10 mL).Concentration yielded a light brown oil (579 mg; 98%) used withoutfurther purification.

MS (ES) m/e 312 (M+H)⁺.

c) 2-[4-amino-2-(trifluoromethyl)phenoxy]-5-ethylphenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for4-(4-ethyl-2-methoxyphenoxy)-3-(trifluoromethyl) aniline (54 mg; 0.170mmol), the title compound (24 mg; 47%) was prepared as a light brownsolid, after purification by preparative TLC (dichloromethane/methanol:98/2).

MS (ES) m/e 298 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 6.95 (d, 1H, J=2.1 Hz); 6.88 (s, 1H); 6.81 (d,1H, J=8.7 Hz); 6.75 (dd, 1H, J₁=2.2 Hz, J₂=8.4 Hz); 6.70 (d, 1H, J=8.2Hz); 6.64 (d, 1H, 8.0 Hz); 2.59 (q, 2H, J=7.6 Hz); 1.22 (t, 3H, 7.6 Hz).

EXAMPLE 21 2-[(2-aminopyridin-3-yl)oxy]-5-ethylphenol a1)3-(4-ethyl-2-methoxyphenoxy)-2-nitropyridine

According to the procedure of example 20(a), except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for3-bromo-2-nitropyridine (2 mmol; 406 mg), the title compound (73 mg;13%) was prepared after chromatography on silica gel (gradientcyclohexane/ethyl acetate).

MS (ES) m/e 275 (M+H)⁺

Alternatively 3-(4-ethyl-2-methoxyphenoxy)-2-nitropyridine can besynthesized using the following procedure:

a2) 3-Fluoro-2-nitropyridine

To a stirred solution of 3-Amino 2-nitro pyridine (2.5 g, 17.97 mmol) indry ethanol (20 ml) was added 10 ml of tetrafluoroboric acid (48% inwater). The reaction mixture was cooled to 0° C. and isoamyl nitrite(2.6 g, 22.4 mmol) was added dropwise at 0° C. and stirred at 0° C. for1 hour. The reaction mixture was filtered, and the solid obtained waswashed with diethyl ether. The filtered solid was added to preheated(150 mL) toluene with stirring and reaction mixture was refluxed for 24hours. The solvent was evaporated and the residue taken in ethyl acetate(200 ml) and washed with water followed by brine, dried over anhydroussodium sulfate and concentrated under reduced pressure to get the crude3-fluoro-2-nitropyridine. This was purified by column over silica gelusing 10% ethyl acetate in pet ether as eluant to get 1 g (39%) of thetitle compound as a yellow solid.

¹H NMR (CDCl₃), δ (ppm): 8.45 (d, J=4.24 Hz, 1H), 7.78-7.83 (m, 1H),7.70-7.74 (m, 1H)

a3) 3-(4-ethyl-2-methoxyphenoxy)-2-nitropyridine

To a stirred solution of 3-Fluoro 2-nitro pyridine (1.6 g, 0.01126 mol)in dry Acetonitrile (20 ml) was added 4-Ethyl-2-methoxy phenol (1.71 g,11.3 mmol) in dry acetonitrile (10 ml) followed by potassium hydroxide(0.696 g, 12.4 mmol). The reaction mixture was heated to 80° C. andmaintained for 2 hours. The solvent was evaporated and taken in ethylacetate (200 ml). The organic layer was washed with water followed bybrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure to give 2.6 g of crude product purified by columnchromatography (5% Ethyl acetate in Petroleum ether) to yield: 1.75 g(56%) of title compound.

b) 3-(4-ethyl-2-methoxyphenoxy)pyridin-2-amine

To a stirred solution of 3-(4-ethyl-2-methoxyphenoxy)-2-nitropyridine(1.3 g, 4.7 mmol) in methanol (30 ml) were added anhydrous Ferricchloride (66 mg) and activated charcoal (66 mg). The resulting mixturewas heated to reflux and Hydrazine hydrate (80%) (2 mL, 39 mmol) wasadded dropwise. The reaction was allowed to stir under reflux conditionfor 5 hours, then filtered through celite. The filtrate was concentratedunder reduced pressure, taken in ethyl acetate (150 ml). The organicphase was washed with water followed by brine, dried over anhydroussodium sulfate and concentrated under reduced pressure to give 1.11 g ofthe title compound, 100% yield.

c) 2-[(2-aminopyridin-3-yl)oxy]-5-ethylphenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for3-(4-ethyl-2-methoxyphenoxy)pyridin-2-amine (63 mg; 0.26 mmol) the titlecompound (13 mg; 22%) was obtained as a light brown oil, after twopurifications by preparative TLC (dichloromethane/methanol: 9/1).

MS (ES) m/e 231 (M+H)⁺

¹H NMR (MeOD) δ (ppm): 7.61 (m, 1H); 6.84 (m, 3H); 6.70 (d, 1H, J=8.2Hz); 6.55 (m, 1H); 2.60 (q, 2H, J=7.5 Hz); 1.23 (t, 3H, J=7.6 Hz)

EXAMPLE 22N-[5-(2-hydroxy-4-propylphenoxy)pyridin-2-yl]methanesulfonamide a)5-(2-methoxy-4-propylphenoxy)-2-nitropyridine

According to the procedure of example 20(a), except substituting1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 5-bromo-2-nitropyridine(406 mg, 2 mmol), the title compound (220 mg; 38%) was prepared as awhite solid, after chromatography on silica gel (gradientcyclohexane/dichloromethane), along with5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine (238 mg; 37%).

MS (ES) m/e 289 (M+H)⁺

b) 5-(2-methoxy-4-propylphenoxy) pyridin-2-amine

According to the procedure of example 20(b), except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for5-(2-methoxy-4-propylphenoxy)-2-nitropyridine (144 mg; 0.5 mmol), thetitle compound (130 mg; 100%) was prepared as a white solid, withoutpurification.

MS (ES) m/e 259 (M+H)⁺

c) 2-[(6-aminopyridin-3-yl)oxy]-5-propylphenol

According to the procedure of example 1(b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for2-[(6-aminopyridin-3-yl)oxy]-5-propylphenol (130 mg, 0.50 mmol), thetitle compound (112 mg, 92%) was prepared as a white solid after washingwith diethyl ether.

MS (ES) m/e 245 (M+H)⁺

¹H NMR (CDCl₃) d (ppm): 7.92 (s, 1H); 7.22 (d, 1H, J=8.8 Hz); 6.90 (s,1H); 6.68 (q, 2H, J=9.3 Hz); 6.54 (d, 1H, J=8.8 Hz); 2.55 (t, 2H, J=7.7Hz); 1.66 (se, 2H, J=7.4 Hz); 0.97 (t, 3H, J=7.3 Hz).

EXAMPLE 23 N-[5-(2-hydroxy-4-propylphenoxy)pyridin-2-yl]methanesulfonamide a) 2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-5-propylphenyl methanesulfonate

To a solution of 2-[(6-aminopyridin-3-yl)oxy]-5-propylphenol (0.12 mmol;30 mg) under argon, in anhydrous dichloromethane (0.5 mL), cooled to−40° C., were added pyridine (0.13 mmol; 0.01 mL) and MsCl (0.12 mmol;0.01 mL). The reaction mixture was stirred overnight while progressivelyheating to room temperature. After quenching with NH₄Cl (1 mL),extraction with ethyl acetate (3*3 mL), combined organic phases werewashed with water (3 mL), dried over MgSO₄, concentrated in vacuo. Thecrude was purified by preparative TLC (dichloromethane/ethyl acetate) toyield the title compound as a white solid (37 mg; 0.09 mmol; 77%).

MS (ES) m/e 401 (M+H)⁺

¹H NMR (acetone-d₆) δ (ppm): 8.16 (s, 1H); 7.52 (d, 1H, J=8.7 Hz); 7.33(s, 1H); 7.22 (t, 2H, J=8.5 Hz); 7.04 (d, 1H, J=7.7 Hz); 3.35 (s, 3H);3.28 (s, 3H); 2.63 (m, 2H); 1.67 (m, 2H); 0.95 (m, 3H).

b) N-[5-(2-hydroxy-4-propylphenoxy)pyridin-2-yl]methane sulfonamide

To a solution of2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-5-propylphenylmethanesulfonate (0.09 mmol; 30 mg), under argon, in water (0.5 mL), wasadded KOH (0.26 mmol; 15 mg). The reaction mixture was refluxed for 4hr. After quenching with NH₄Cl (1 mL), extraction with ethyl acetate(3*3 mL), combined organic phases were washed with water (3 mL), driedover MgSO₄, concentrated in vacuo, to yield the title compound as awhite solid (37 mg; 0.09 mmol; 77%).

MS (ES) m/e 323 (M+H)⁺

¹H NMR (acetone-d₆) δ (ppm): 7.99 (d, 1H, J=13.2 Hz); 7.31 (d, 1H, J=9.1Hz); 7.16 (d, 1H, J=9.0 Hz); 6.94 (d, 1H, J=7.8 Hz); 6.89 (s, 1H); 6.73(d, 1H, J=7.3 Hz); 3.24 (s, 3H); 2.80 (s, 3H); 2.54 (t, 2H, J=6.8 Hz);1.64 (se, 2H, J=6.4 Hz); 0.95 (t, 3, J=6.3 Hz).

EXAMPLE 24 2-[(6-ethoxypyridin-3-yl)oxy]-5-propylphenol a)5-(2-hydroxy-4-propylphenoxy)pyridin-2-ol

To a solution of 2-[(6-aminopyridin-3-yl)oxy]-5-propylphenol (0.20 mmol;50 mg) under argon, in H₂SO₄ (35%; 0.2 mL), cooled to 0° C., was slowlyadded NaNO₂ (0.26 mmol; 18 mg) in water (0.2 mL). After 30 min, CuSO₄ (3mmol; 477 mg) in water (1 mL), then Cu₂O (0.18 mmol; 26 mg) were added.After 30 min, the mixture was neutralised with NaHCO₃ sat. (1 mL),extracted with ethyl acetate (3*3 mL). Combined organic phases werewashed with analytical sample was obtained by preparative TLC to yieldthe title compound as a white solid (5 mg; 0.02 mmol; ca 20%).

MS (ES) m/e 246 (M+H)⁺

¹H RMN (CD₃OD) δ (ppm): 7.48 (dd, 1H, J, =9.8 Hz, J₂=3.2 Hz); 7.01 (d,1H, J=3.1 Hz); 6.80 (d, 1H, J=8.2 Hz); 6.76 (d, 1H, J=1.9 Hz); 6.63 (dd,1H, J, =8.1 Hz, J₂=2.0 Hz); 6.54 (d, 1H, J=9.8 Hz); 2.48 (t, 2H, J=7.8Hz); 1.60 (se, 2H, J=7.5 Hz); 0.91 (t, 3H, J=7.4 Hz).

b) 5-(2-ethoxy-4-propylphenoxy)-1-ethylpyridin-2 (1H)-one

To a solution of 5-(2-hydroxy-4-propylphenoxy)pyridin-2-ol (0.08 mmol;20 mg) under argon, in anhydrous DMF (0.5 mL) cooled to 0° C., wereadded LiOH (0.09 mmol; 2 mg), then EtBr (0.09 mmol; 0.007 mL). Afterallowing the mixture to warm overnight up to room temperature, thereaction was neutralised with NaHCO₃ (1 mL), extracted with ethylacetate (3*3 mL). Combined organic phases were washed with water (3 mL),dried over MgSO₄, concentrated in vacuo to yield the title compound as abrown oil (14 mg; 0.05 mmol; 58%), used as such.

MS (ES) m/e 302 (M+H)⁺

c) 2-[(6-ethoxypyridin-3-yl)oxy]-5-propylphenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for5-(2-ethoxy-4-propylphenoxy)-1-ethylpyridin-2(1H)-one (14 mg; 0.05mmol), the title compound (7 mg; 51%) was prepared as a white solid,after purification by preparative TLC (dichloromethane/ethyl acetate).

MS (ES) m/e 274 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.23 (d, 1H, J=6.8 Hz); 7.10 (s, 1H); 6.86 (s,1H); 6.69 (d, 1H, J=8.0 Hz); 6.63 (d, 1H, J=8.0 Hz); 6.58 (d, 1H, J=9.8Hz); 3.95 (q, 2H, J=7.1 Hz); 2.51 (t, 2H, J=7.7 Hz); 1.62 (se, 2H, J=7.8Hz); 1.34 (t, 3H, J=7.2 Hz); 0.92 (t, 3H, J=7.3 Hz).

EXAMPLE 25 2-[(4,6-difluoropyridin-2-yl)oxy]-5-propylphenol (25A) and2-[(2,6-difluoropyridin-4-yl)oxy]-5-propylphenol (25B) a)2,4-difluoro-6-(2-methoxy-4-propylphenoxy)pyridine and2,6-difluoro-4-(2-methoxy-4-propylphenoxy)pyridine

According to the procedure of example 5(a) except substituting2,6-difluoropyridine for 2,4,6-trifluoropyridine (0.32 mL, 2 mmol), thetitle compounds (265 mg; 47%) were prepared together as a clear oil,after purification by silica gel chromatography (gradientcyclohexane/dichloromethane).

MS (ES) m/e 280 (M+H)⁺

b) 2-[(4,6-difluoropyridin-2-yl)oxy]-5-propylphenol (25A) and2-[(2,6-difluoropyridin-4-yl)oxy]-5-propylphenol (25B)

According to the procedure of example 5 (b), except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for2,4-difluoro-6-(2-methoxy-4-propylphenoxy)pyridine and2,6-difluoro-4-(2-methoxy-4-propylphenoxy)pyridine (67 mg, 0.24 mmol),title compound A, as a white solid (11 mg; 17%), and title compound B asa clear oil (22 mg; 35%) were prepared after purification by preparativeTLC (dichloromethane/ethyl acetate).

A: MS (ES) m/e 266 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 7.01 (d, 1H, J=8.2 Hz); 6.92 (s, 1H); 6.77 (d,1H, J=8.3 Hz); 6.49 (d, 1H, J=8.7 Hz); 6.41 (d, 1H, J=7.7 Hz); 5.72 (br,1H); 2.57 (t, 2H, J=7.8 Hz); 1.67 (se, 2H, J=7.3 Hz); 0.97 (t, 3H, J=7.3Hz).

B: MS (ES) m/e 266 (M+H)⁺

NMR¹H (CDCl₃) δ (ppm): 6.97 (d, 1H, J=8.2 Hz); 6.92 (s, 1H); 6.80 (d,1H, J=8.3 Hz); 6.36 (s, 2H); 5.37 (br, 1H); 2.58 (t, 2H, J=7.8 Hz); 1.68(se, 2H, J=7.6 Hz); 0.97 (t, 3H, J=7.4 Hz).

EXAMPLE 262-[(6-fluoropyridin-2-yl)oxy]-5-(2,2,2-trifluoro-1-hydroxyethyl)phenola)2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}ethanol

To a solution of 4-[(6-fluoropyridin-2-yl)oxy]-3-methoxy benzaldehyde(300 mg; 1.2 mmol) with trifluoro methyltrimethylsilane (228 μl; 1.46mmol) in THF (3 ml) under argon at 0° C. was added a molar solution ofTBAF in THF (10 μl; 0.012 mmol). The reaction mixture was allowed tostir at rt for 2 h and a molar aqueous solution of HCl was addeddropwise (2.5 ml; 2.5 mmol). The reaction mixture was stirred foranother 2 h. water and diethylether were added. The aqueous phase wasfurther extracted (2×EtOAc). Combined organic phases were dried overMgSO₄, concentrated in vacuo to afford the title compound as a whitesolid (333 mg; 1.05 mmol; 88%).

¹H NMR (CDCl₃) δ (ppm): 7.79 (q, 1H, J=8.0 Hz); 7.24-7.20 (m, 2H);7.17-7.09 (m, 1H); 6.81 (d, 1H, J=8.0 Hz); 6.64 (d, 1H, J=7.8 Hz); 5.10(m, 1H); 3.85 (s, 3H).

b) 2-[(6-fluoropyridin-2-yl)oxy]-5-(2,2,2-trifluoro-1-hydroxyethyl)phenol

According to the procedure of example 5 (b) except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine by2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3 methoxyphenyl}ethanol(0.15 mmol; 50 mg) and adding 3.5 equivalents (0.47 mmol; 470 μl) ofboron tribromide, the title compound was prepared in 84% yield (0.13mmol; 38 mg) after purification by preparative TLC on silica gel (ethylacetate/cyclohexane—40/60).

MS (ES) 304 [M+1]⁺

¹H NMR (DMSO) δ (ppm): 9.79 (s, 1H); 7.97 (q, 1H, J=8.3 Hz); 7.12 (s,1H); 7.11 (d, 1H, J=8.1 Hz); 6.96 (d, 1H, J=9.1 Hz); 6.85 (d, 1H, J=8.0Hz); 6.81 (d, 2H, J=5.4 Hz); 5.11 (qt, 1H).

EXAMPLE 27 2-[(6-fluoropyridin-2-yl)oxy]-5-(2,2,2-trifluoroethyl)phenola) 2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}ethyl 4-methylbenzenesulfonate

To a solution of2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}ethanol(0.52 mmol; 165 mg), tosyl chloride (0.57 mmol; 109 mg) and DMAP (0.01mmol; 1.5 mg) under argon in dichloromethane (4 mL) at 0° C. was addedTEA (1.04 mmol; 145 μl). The reaction mixture was stirred at rt for 3 h,then washed with brine (2×), dried over MgSO₄, concentrated and purifiedby preparative TLC on silica gel (ethyl acetate/cyclohexane—30/70) toyield the title compound (101 mg; 0.21 mmol; 41%).

¹H NMR (CDCl₃) δ (ppm): 7.78 (q, 1H, J=8.6 Hz); 7.65 (d, 2H, J=8.2 Hz);7.29 (d, 2H, J=8.6 Hz); 7.06 (d, 1H, J=8.2 Hz); 6.92 (d, 1H, J=9.7 Hz);6.86 (s, 1H); 6.77 (d, 1H, J=8.0 Hz); 6.63 (d, 1H, J=8.1 Hz); 5.69 (q,1H, J=6.3 Hz); 3.67 (s, 3H); 2.40 (s, 3H).

b) 2-fluoro-6-[2-methoxy-4-(2,2,2-trifluoroethyl)phenoxy]pyridine

A solution of2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}ethyl4-methylbenzenesulfonate (0.2 mmol; 96 mg) in ethanol (3 ml) containinga catalytic amount of Pd/C (10% wet; 0.014 mmol; 30 mg) was stirred for16 h at rt under 2.5 atm of hydrogen. Purification by preparative TLC onsilica gel (ethyl acetate/cyclohexane—30/70) afforded the title compound(48 mg; 0.16 mmol; 80%).

MS (ES) 302 [M+1]⁺

¹H NMR (CDCl₃) δ (ppm): 7.75 (q, 1H, J=7.9 Hz); 7.13 (d, 1H, J=8.5 Hz);6.96-6.90 (m, 2H); 6.76 (d, 1H, J=7.3 Hz); 6.59 (d, 1H, J=7.9 Hz); 3.80(s, 3H); 3.40 (q, 1H, J=10.9 Hz).

c) 2-[(6-fluoropyridin-2-yl)oxy]-5-(2,2,2-trifluoroethyl) phenol

According to the procedure of example 5 (b) except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine by2-fluoro-6-[2-methoxy-4-(2,2,2-trifluoroethyl)phenoxy]pyridine (0.14mmol; 43 mg) and adding 3.5 equivalents (0.5 mmol; 500 μl) of borontribromide, the title compound was prepared in 75% yield (0.11 mmol; 30mg) after purification by preparative TLC on silica gel (ethylacetate/cyclohexane—30/70).

MS (ES) 288 [M+1]⁺

¹H NMR (CDCl₃) δ (ppm): 7.84 (q, 1H, J=7.6 Hz); 7.12 (d, 1H, J=8.7 Hz);7.05 (s, 1H); 6.89-6.82 (m, 2H); 6.71 (d, 1H, J=6.3 Hz); 6.02 (s br,1H); 3.36 (q, 1H, J=10.3 Hz).

EXAMPLE 28 2-[(6-fluoropyridin-2-yl)oxy]-5-(trifluorovinyl) phenol a)2-fluoro-6-[2-methoxy-4-(1,2,2,2 tetrafluoroethyl)phenoxy]pyridine

To a solution of2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}ethanol(0.22 mmol; 70 mg) under argon in dichloromethane (2 mL) at −78° C. wasadded dropwise DAST (0.22 mmol; 29 μl). The reaction mixture was letcome back to rt for 2 h and quenched with brine (3 ml). The aqueousphase was collected, neutralized with sodium bicarbonate and extractedtwice with chloroform. The organic phases were combined, dried overMgSO₄, concentrated and purified by preparative TLC on silica gel (ethylacetate/cyclohexane—30/70) to yield the title compound (25 mg; 0.08mmol; 37%).

¹H NMR (CDCl₃) δ (ppm): 7.78 (q, 1H, J=8.1 Hz); 7.22 (d, 1H, J=8.0 Hz);7.10 (m, 2H); 6.80 (d, 1H, J=8.0 Hz); 6.62 (d, 1H, J=7.8 Hz); 5.62 (dq,1H, J=37.8 and 6.2 Hz); 3.82 (s, 3H).

b) 2-fluoro-6-[2-methoxy-4-(trifluorovinyl)phenoxy]pyridine

To a solution of2-fluoro-6-[2-methoxy-4-(1,2,2,2-tetrafluoroethyl)phenoxy]pyridine(0.078 mmol; 25 mg) under argon in THF (1 mL) at 0° C. was addeddropwise a one molar solution of LiHMDS in THF (0.094 mmol; 94 μl). Thereaction mixture was let come back to rt for 16 h. Concentration andpurification by preparative TLC on silica gel (ethylacetate/cyclohexane—30/70) afforded the title compound (10 mg; 0.033mmol; 43%).

¹H NMR (CDCl₃) δ (ppm): 7.73 (q, 1H, J=7.9 Hz); 7.21 (d, 1H, J=8.1 Hz);7.12 (d, 1H, J=9.9 Hz); 7.11 (s, 1H); 6.80 (d, 1H, J=7.9 Hz); 6.61 (d,1H, J=7.7 Hz); 3.81 (s, 3H).

c) 2-[(6-fluoropyridin-2-yl)oxy]-5-(trifluorovinyl) phenol

According to the procedure of example 5 (b) except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine by2-fluoro-6-[2-methoxy-4-(trifluorovinyl)phenoxy]pyridine (0.033 mmol; 10mg) and adding 3.5 equivalents (0.117 mmol; 117 μl) of boron tribromide,the title compound was prepared in 64% yield (0.021 mmol; 6 mg) afterpurification by preparative TLC on silica gel (ethylacetate/cyclohexane—30/70).

¹H NMR (CDCl₃) δ (ppm): 7.76 (q, 1H, J=8.0 Hz); 7.13 (d, 1H, J=1.9 Hz);7.11 (d, 1H, J=8.6 Hz); 6.98 (d, 1H, J=10.0 Hz); 6.80 (d, 1H, J=8.0 Hz);6.63 (d, 1H, J=9.6 Hz); 6.00 (s br, 1H).

EXAMPLE 29 1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone a)1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]ethanone

According to the procedure of example 4 (a) except substituting2,6-Difluoropyridine for 1-(3,4-difluorophenyl)ethanone (0.77 mmol; 0.97ml), the title compound was isolated as a light brown oil (244 mg;quantitative) used without purification.

MS (ES) m/e 289 (M+H)⁺

b) 1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]ethanone (244 mg; 0.70mmol), an analytical sample of the title compound (11 mg;

5%) was prepared as a light brown oil, after purification by preparativeTLC (cyclohexane/ethyl acetate: 7/3). MS (ES) m/e 275 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 9.38 (dd, 1H, J₁=2.0 Hz, J₂=11.6 Hz); 7.65 (d,1H, J=8.4 Hz); 6.95 (t, 2H, J=8.0 Hz); 6.85 (d, 1H, J=8.1 Hz); 6.72 (d,1H, J=8.0 Hz); 5.59 (s1, 1H); 2.62 (q, 2H, J=7.6 Hz); 2.56 (s, 3H); 1.24(t, 3H, J=7.5 Hz).

EXAMPLE 30 (1E)-1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone-O-methyloxime

To a solution of 1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone(46 mg; 0.17 mmol), under argon, in ethanol (1 mL), was addedO-methylhydroxylamine hydrochloride (14 mg; 0.17 mmol) and 0.05 mL oftriethylamine. The reaction was stirred to room temperature overnight.The mixture was concentrated in vacuo to give the desired product aslight brown oil after purification by preparative TLC (14.5 mg; 0.048mmol; 28%).

¹H NMR (CDCl₃) δ (ppm): 7.53 (dd, 1H, J₁=1.9 Hz, J₂=12.0 Hz); 7.33 (d,1H, J=8.5 Hz); 6.99 (t, 1H, J=8.5 Hz); 6.90 (d, 1H, J=1.5 Hz); 6.75 (d,1H, J=8.3 Hz); 6.66 (dd, 1H, J₁=1.4 Hz, J₂=8.2 Hz); 5.54 (s, 1H); 3.99(s, 3H); 2.60 (q, 2H, J=7.6 Hz); 2.19 (s, 3H); 1.23 (t, 3H, J=7.6 Hz).

EXAMPLE 312-[(6-fluoropyridin-2-yl)oxy]-5-(1H-imidazol-1-ylmethyl)phenol a)2-[4-(chloromethyl)-2-methoxyphenoxy]-6-fluoro pyridine

To a solution of {4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}methanol(367 mg; 1.47 mmol), under argon, in dichloromethane (6 mL), cooled to−40° C., was added pyridine (131 μL; 1.62 mmol) then methanesulfonylchloride (115 μL; 1.47 mmol). The reaction mixture was allowed to stirfor 6 hr, with gradual warming to room temperature. The mixture wascooled to −40° C., pyridine (50 μL; 0.62 mmol) and methanesulfonylchloride (40 μL; 0.51 mmol) were added. The reaction was stirredovernight, with gradual warming to room temperature.

The reaction was hydrolysed with saturated NH₄Cl (10 mL), extracted withethyl acetate (2*5 mL). Combined organic phases were dried over Na₂SO₄,concentrated in vacuo. The title compound (185 mg; 47%) was obtained asa light oil, after purification on silica gel (cyclohexane/ethylacetate: 95/5).

¹H NMR (CDCl₃) δ (ppm): 7.75 (q, 1H, J=7.6 Hz); 7.10 (d, 1H, J=7.9 Hz);7.04 (s, 1H); 7.00 (d, 1H, J=8.1 Hz); 6.74 (d, 1H, J=7.9 Hz); 6.57 (dd,1H, J₁=7.8 Hz, J₂=1.8 Hz); 4.60 (s, 2H); 3.79 (s, 3H).

b) 2-fluoro-6-[4-(1H-imidazol-1-ylmethyl)-2-methoxyphenoxy]pyridine

To a solution of imidazole (18 mg; 0.27 mmol) and NaH (12 mg; 0.30 mmol)in DMF (1 mL), under argon, was added a solution of2-[4-(chloromethyl)-2-methoxyphenoxy]-6-fluoropyridine (65 mg; 0.24mmol) in DMF (1 mL). The reaction mixture was allowed to stir overnight,to 40° C. After concentration, the reaction was hydrolysed withsaturated NH₄Cl (1 mL), extracted with AcOEt (2*1 mL). Combined organicphases were dried over Na₂SO₄, concentrated in vacuo, the title compound(68 mg; 93%) was obtained.

c) 2-[(6-fluoropyridin-2-yl)oxy]-5-(1H-imidazol-1-ylmethyl) phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for2-fluoro-6-[4-(1H-imidazol-1-ylmethyl)-2-methoxy phenoxy]pyridine (68mg; 0.23 mmol), the title compound (16 mg; 24%) was obtained as a whitesolid, after purification by preparative TLC (dichloromethane/methanol:9/1).

MS (ES) m/e 286 (M+H)⁺

¹H NMR (MeOD) δ (ppm): 7.93 (m, 2H); 7.28 (s1, 1H); 7.12 (m, 2H); 6.84(m, 3H); 6.72 (dd, 1H, J, =7.8 Hz, J₂=2.0 Hz); 5.27 (s, 2H).

EXAMPLE 322-[(6-fluoropyridin-2-yl)oxy]-5-(1H-1,2,4-triazol-1-ylmethyl)phenol a)2-fluoro-6-[2-methoxy-4-(1H-1,2,4-triazol-1-ylmethyl) phenoxy]pyridine

To a solution of triazole (18 mg; 0.267 mmol) and NaH (10 mg; 0.25 mmol)in DMF (1 mL), under argon, was added a solution of2-[4-(chloromethyl)-2-methoxyphenoxy]-6-fluoropyridine (65 mg; 0.243mmol) in DMF (1 mL). The reaction mixture was allowed to stir overnightat 40° C. After concentration, the reaction was hydrolysed withsaturated NH₄Cl (1 mL), extracted with AcOEt (2*1 mL). Combined organicphases were dried over Na₂SO₄, concentrated in vacuo, the title compound(72 mg; quantitative) was obtained.

b) 2-[(6-fluoropyridin-2-yl)oxy]-5-(1H-1,2,4-triazol-1-yl methyl)phenol

According to the procedure of example 1(b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine by2-fluoro-6-[2-methoxy-4-(1H-1,2,4-triazol-1-ylmethyl)phenoxy]pyridine(71 mg; 0.24 mmol), the title compound was prepared (37 mg; 54%) afterpurification by preparative TLC on silica gel(dichloromethane/methanol—9/1).

¹H NMR (MeOD) δ (ppm): 8.75 (s, 1H); 8.08 (s, 1H); 7.74 (q, 1H, J=7.7Hz); 6.95 (d, 1H, J=8.2 Hz); 6.82 (d, 1H, J=1.8 Hz); 6.76 (dd, 1H, J,=8.1 Hz, J₂=1.8 Hz); 6.64 (dd, 1H, J, =8.0 Hz, J₂=1.0 Hz); 6.55 (dd, 1H,J₁=7.8 Hz, J₂=2.2 Hz); 5.32 (s, 2H).

EXAMPLE 33 5-ethyl-2-[(6-fluoropyridin-2-yl)oxy]phenyl acetate

To a solution of 5-Ethyl-2-(6-fluoro-pyridin-2-yloxy)-phenol (20 mg;0.09 mmol), under argon, in dimethylformamide (2 mL), cooled to 0° C.,was added triethylamine (36 μL; 0.26 mmol) and acetic acid (10 μL; 0.18mmol). The reaction mixture was allowed to stir overnight, with gradualwarming to room temperature. The reaction was concentrated, diluted withsaturated NaHCO₃ (5 mL) and extracted with ethyl acetate (3*3 mL).Combined organic phases were dried over Na₂SO₄, concentrated in vacuo,the title compound (8 mg; 34%) was obtained as clear oil, afterpurification on neutral alumina gel (cyclohexane/ethyl acetate: 9/1).

¹H RMN (CDCl₃) (ppm): 7.73 (q, 1H, J=8.0 Hz); 7.11 (m, 2H); 6.72 (d, 1H,J=8.0 Hz); 6.60 (dd, 1H, J₁=7.8 Hz, J₂=2.4 Hz); 2.67 (q, 2H, J=7.6 Hz);2.11 (s, 3H); 1.26 (t, 3H, J=7.6 Hz).

EXAMPLE 34 2-(2-aminophenoxy)-5-ethylphenol a)4-ethyl-2-methoxy-1-(2-nitrophenoxy)benzene

According to the procedure of example 21 (a3) except substituting3-Fluoro 2-nitro pyridine by 2-fluoronitrobenzene (0.72 mmol; 102 mg),the title compound was prepared in quantitative yield (205 mg) and usedwithout further purification.

MS (ES) m/e 274 (M+H)⁺

b) 2-(4-ethyl-2-methoxyphenoxy)aniline

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene by4-ethyl-2-methoxy-1-(2-nitrophenoxy)benzene (0.66 mmol; 180 mg) and THFby ethanol, the title compound was prepared in quantitative yield (181mg) and used without further purification.

MS (ES) m/e 244 (M+H)⁺

c) 2-(2-aminophenoxy)-5-ethylphenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine by2-(4-ethyl-2-methoxyphenoxy)aniline (50 mg; 0.21 mmol), the titlecompound was prepared in 42% yield (0.09 mmol; 20 mg) after purificationby preparative TLC on silica gel (dichloromethane/methanol—40/60).

MS (ES) m/e 244 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 6.93 (t, 1H, J=7.4 Hz); 6.89-6.85 (m, 2H);6.82-6.79 (m, 2H); 6.76-6.72 (m, 1H) 6.64 (dd, 1H, J₁=8.1 Hz; J₂=1.8Hz); 2.58 (q, 2H, J=7.6 Hz); 1.22 (t, 3H, J=7.6 Hz).

EXAMPLE 36 2-[(6-fluoropyridin-2-yl)oxy]-5-(methoxymethyl) phenol a)5-(chloromethyl)-2-[(6-fluoropyridin-2-yl)oxy]phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine by2-[4-(chloromethyl)-2-methoxyphenoxy]-6-fluoro pyridine (205 mg; 0.77mmol), the title compound (185 mg; 95%) was prepared as a light brownsolid without further purification.

MS (ES) m/e 254 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 7.81 (q, 1H, J=8.0 Hz); 7.11 (m, 2H); 6.95 (dd,1H, J₁=8.2 Hz, J₂=1.9 Hz); 6.83 (d, 1H, J=8.0 Hz); 6.68 (dd, 1H, J₁=7.9Hz, J₂=2.1 Hz); 4.55 (s, 2H).

b) 2-[(6-fluoropyridin-2-yl)oxy]-5-(methoxymethyl)phenol

To a solution of 5-(chloromethyl)-2-[(6-fluoropyridin-2-yl)oxy]phenol(50 mg; 0.20 mmol), under argon, in methanol (1 mL) was added sodiummethoxylate (3.94 mmol; 22 mg) and sodium iodide (0.07 mmol; 10 mg). Thereaction mixture was allowed to stir at room temperature overnight. Thereaction was hydrolysed with saturated NH₄Cl (5 mL), extracted withethyl acetate (3*2 mL), and washed with 5 mL of saturated NaHCO₃.Combined organic phases were dried over Na₂SO₄, concentrated in vacuo,the title compound (49 mg; 100%) was prepared as a light yellow oilwithout further purification.

MS (ES) m/e 250 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 7.77 (q, 1H, J=8.0 Hz); 7.07 (m, 2H); 6.89 (dd,1H, J₁=8.1 Hz, J₂=1.3 Hz); 6.77 (d, 1H, J=7.8 Hz); 6.65 (dd, 1H, J₁=7.8Hz, J₂=2.1 Hz); 4.42 (s, 2H); 3.40 (s, 3H).

EXAMPLE 37 5-ethyl-2-{2-fluoro-4-[(4-hydroxybutyl)amino]phenoxy}phenola) 4-ethyl-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene

According to the procedure of example 20(a) except substituting1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 3,4-difluoronitrobenzene(318 mg; 2.0 mmol), the title compound (551 mg; 95%) was prepared as ayellow solid, used without further purification.

MS (ES) m/e 292 (M+H)⁺.

b) 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline and4-{[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]amino}butan-1-ol

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for4-ethyl-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene (551 mg; 1.89mmol), two compounds were obtained after purification on silica gel(gradient: cyclohexane/ethyl acetate):

4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (202 mg; 40%)

MS (ES) m/e 262 (M+H)⁺.

4-{[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]amino}butan-1-ol (30 mg;5%) MS (ES) m/e 334 (M+H)⁺.

c) 5-ethyl-2-{2-fluoro-4-[(4-hydroxybutyl)amino]phenoxy}phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for4-{[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]amino}butan-1-ol (30 mg;0.009 mmol), the title compound (24 mg; 83%) was prepared as a lightbrown solid, after purification by preparative TLC(dichloromethane/methanol: 95/5).

MS (ES) m/e 320 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 6.90 (m, 2H); 6.60 (m, 2H); 6.42 (d, 1H, J=12.8Hz); 6.33 (d, 1H, J=8.7 Hz); 3.71 (m, 2H); 3.12 (t, 2H, J=5.9 Hz); 2.56(q, 2H, J=7.6 Hz); 1.70 (s1, 4H); 1.20 (t, 3H, J=7.6 Hz).

EXAMPLE 382-{3-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-1,3-dionea) 4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenol

To a solution of 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (215 mg;0.82 mmol) in H₂SO₄ 35%, at 0° C., was added a solution of NaNO₂ (69 mg;1 mmol) in water (1 mL). The mixture was stirred 30 min. at 0° C. Asolution of copper(II) sulphate (1.85 g; 11.6 mmol) in 6 mL of water wasadded, followed by copper(I) oxide (99 mg; 0.69 mmol). The reaction wasstirred 45 min. at room temperature, then hydrolysed with NaHCO₃ sat (6mL) and NH₄OH. The mixture was extracted with ethyl acetate (3*5 mL).Combined organic phases were dried over Na₂SO₄, concentrated in vacuo.The title compound (85 mg; 0.032 mmol; 39%) was obtained as an oil,after purification by preparative TLC (cyclohexane/ethyl acetate: 7/3).

MS (ES) m/e 285 (M+Na)⁺

b)2-{3-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-1,3-dione

To a solution of 4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenol (0.32 mmol;85 mg) in dry acetone (3 mL), under argon, were added potassiumhydroxide (0.39 mmol; 54 mg), NaI (0.065 mmol; 10 mg) andN-(3-bromopropyl)phtalimide (0.40 mmol; 107 mg). The reaction wasstirred 3 days at 50° C. The mixture was concentrated in vacuo,hydrolysed with NH₄Cl sat. (5 mL) and extracted with ethyl acetate (3*3mL). Combined organic phases were dried over Na₂SO₄, concentrated invacuo. The title compound (75 mg; 0.17 mmol; 51%) was obtained as anoil, after purification by preparative TLC (cyclohexane/ethyl acetate:7/3).

MS (ES) m/e 285 (M+Na)⁺

¹H RMN (CDCl₃) δ (ppm): 7.83 (dd, 2H, J, =5.2 Hz; J₂=3.0 Hz); 7.71 (dd,2H, J, =5.2 Hz; J₂=2.9 Hz); 6.86 (t, 1H, J=9.1 Hz); 6.80 (s, 1H); 6.67(s, 2H); 6.61 (dd, 1H, J₁=12.1 Hz; J₂=2.5 Hz); 6.50 (d, 1H, J=8.9 Hz);3.98 (t, 2H, J=5.9 Hz); 3.91-3.87 (m, 5H); 2.61 (q, 2H, J=7.6 Hz);2.20-2.16 (m, 2H); 1.23 (t, 3H, J=7.6 Hz).

c)2-{3-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-1,3-dione

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine by2-{3-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-1,3-dione(64 mg; 0.14 mmol), the title compound was prepared in 83% yield (0.12mmol; 52 mg) after purification by preparative TLC on silica gel (ethylacetate/cyclohexane—30/70).

MS (ES) m/e 436 (M+H)⁺

¹H RMN (CDCl₃) b (ppm): 7.84 (dd, 2H, J₁=5.4 Hz; J₂=3.1 Hz); 7.71 (dd,2H, J₁=5.4 Hz; J₂=3.0 Hz); 6.94 (t, 1H, J=9.0 Hz); 6.86 (s, 1H);6.63-6.60 (m, 2H); 6.54-6.50 (m, 1H); 3.98 (t, 2H, J=5.9 Hz); 3.90 (t,2H, J=6.8 Hz); 2.56 (q, 2H, J=7.6 Hz); 2.17 (qt, 2H, J=6.2 Hz); 1.20 (t,3H, J=7.6 Hz).

EXAMPLE 39 2-[4-(3-aminopropoxy)-2-fluorophenoxy]-5-ethyl phenol

To a solution of2-{3-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-1,3-dione(0.096 mmol; 42 mg) in methanol (2 mL), under argon, was added hydrazinemonohydrate (0.21 mmol; 10 μL). The reaction was heated to reflux for 1h 30. After cooling to 0° C., the mixture was hydrolysed with HCl 1N andfiltered. The filtrate was basified with NaOH 0.1 N (pH=11) andextracted with chloroform (3*5 mL). Combined organic phases were driedover Na₂SO₄, concentrated in vacuo. The title compound (13 mg; 0.04mmol; 44%) was obtained as yellow oil, after purification by preparativeTLC (dichloromethane/methanol/NH₄OH: 90/10/1).

MS (ES) m/e 306 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 6.92 (t, 1H, J=9.1 Hz); 6.85 (s, 1H); 6.68 (dd,1H, J₁=12.1 Hz, J₂=2.6 Hz); 6.63-6.56 (m, 3H); 3.90 (t, 2H, J=6.8 Hz);3.86 (s1, 2H); 2.96 (s1, 2H); 2.56 (q, 2H, J=7.6 Hz); 1.97 (qt, 2H,J=6.2 Hz); 1.19 (t, 3H, J=7.6 Hz).

EXAMPLE 401-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl-eth-(E)-ylideneaminooxy]-aceticacid ethyl ester

According to the procedure of example 30 except substitutingO-methylhydroxylamine hydrochloride by (aminooxy)acetic acidhydrochloride (0.21 mmol; 23 mg), the title compound was isolated (43mg; 65%) after purification by preparative (ethylacetate/cyclohexane/acetic acid—40/60/1).

MS (ES) m/e 376 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.51 (dd, 1H, J, =12.0 Hz, J₂=1.9 Hz); 7.32 (d,1H, J=8.0 Hz); 6.96 (t, 1H, J=8.4 Hz); 6.89 (s, 1H); 6.75 (d, 1H, J=8.3Hz); 6.66 (dd, 1H, J, =8.2 Hz, J₂=1.6 Hz); 4.72 (s, 2H); 4.24 (q, 2H,J=7.1 Hz); 2.60 (q, 2H, J=7.6 Hz); 2.27 (s, 3H); 1.29 (t, 3H, J=7.1 Hz);1.22 (t, 3H, J=7.6 Hz).

EXAMPLE 41[({(1E)-1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethylidene}amino)oxy]aceticacid

The title compound (11 mg; 18%) was isolated from the example as a whitesolid, after purification by preparative TLC ethylacetate/cyclohexane/acetic acid—40/60/1).

MS (ES) m/e 348 (M+H)⁺

¹H RMN (MeOD) δ (ppm): 7.52 (d, 1H, J=12.5 Hz); 7.33 (d, 1H, J=8.3 Hz);6.83-6.80 (m, 2H); 6.77 (t, 1H, J=8.0 Hz); 6.68 (dd, 1H, J₁=8.2 Hz,J₂=1.8 Hz); 4.86 (s1, 2H); 2.59 (q, 2H, J=7.6 Hz); 2.26 (s, 3H); 1.23(t, 3H, J=7.6 Hz).

EXAMPLE 42 3-Morpholin-4-yl-propane-1-sulfonic acid[4-(4-ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl]-amide a)3-chloro-N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]propane-1-sulfonamide

To a solution of 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (0.38mmol; 100 mg) in dry dichloromethane (1 mL), under argon, at 0° C. wereadded pyridine (0.46 mmol; 37 μL) and 3-chloropropanesulfonyle chloride(0.46 mmol; 56 μL). The reaction was stirred overnight at roomtemperature. The mixture was hydrolysed with NH₄Cl sat. (2 mL) andextracted with dichloromethane (3*1 mL). Combined organic phases weredried over Na₂SO₄, concentrated in vacuo. The title compound (200 mg;0.38 mmol; quantitative) was obtained as a brown oil, used withoutfurther purification.

MS (ES) m/e 306 (M+H)⁺

b)3-Morpholin-4-yl-propane-1-sulfonicacid[4-(4-ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-amide

To a solution of3-chloro-N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]propane-1-sulfonamide(0.38 mmol; 153 mg) in dry acetonitrile (2 mL), under argon, was addedmorpholine (1.1 mmol; 100 μL). The reaction was heated at 50° C.overnight. After cooling to room temperature, the mixture was hydrolysedwith 5 mL of water and extracted with dichloromethane (3*2 mL). Combinedorganic phases were dried over Na₂SO₄, concentrated in vacuo, the titlecompound (62 mg; 36%) was obtained after purification by preparative TLCon silica gel (ethyl acetate/cyclohexane—40/60).

MS (ES) m/e 453 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.11 (dd, 1H, J, =12.0 Hz, J₂=2.1 Hz); 6.84-6.72(m, 5H); 3.83 (s, 3H); 3.69 (m, 4H); 3.19 (t, 2H, J 7.1 Hz); 2.64 (q,2H, J=7.6 Hz); 2.51-2.47 (m, 6H); 2.04 (qt, 2H, J=6.8 Hz); 1.25 (t, 3H,J=7.6 Hz).

c) 3-Morpholin-4-yl-propane-1-sulfonic acid[4-(4-ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl]-amide

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine by3-Morpholin-4-yl-propane-1-sulfonicacid[4-(4-ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-amide(0.11 mmol; 50 mg), the title compound was prepared in 60% yield (0.07mmol; 29 mg) after purification by preparative TLC(dichloromethane/methanol-95/5).

MS (ES) m/e 439 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.16 (dd, 1H, J, =11.7 Hz, J₂=2.3 Hz); 6.95-6.88(m, 3H); 6.73 (d, 1H, J=8.2 Hz); 6.65 (dd, 1H, J₁=8.2 Hz, J₂=1.9 Hz);3.71 (t, 4H, J=4.2 Hz); 3.18 (t, 2H, J=7.0 Hz); 2.61-2.53 (m, 8H); 2.06(qt, 2H, J=6.8 Hz); 1.21 (t, 3H, J=7.6 Hz).

EXAMPLE 432-[4-(1,1-Dioxo-isothiazolidin-2-yl)-2-fluoro-phenoxy]-5-ethyl-phenol a)2-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-isothiazolidine1,1-dioxide

The title compound (44 mg; 31%) was isolated from the example (b) as awhite solid, after purification by preparative TLC on silica gel (ethylacetate/cyclohexane—40/60).

MS (ES) m/e 388 (M+Na)⁺

¹H RMN (CDCl₃) δ (ppm): 7.11 (dd, 1H, J, =12.0 Hz, J₂=2.5 Hz); 6.94 (d,1H, J=8.9 Hz); 6.87-6.80 (m, 3H); 6.72 (dd, 1H, J, =8.1 Hz, J₂=1.3 Hz);3.83 (s, 3H); 3.71 (t, 2H, J=6.6 Hz); 3.38 (t, 2H, J=7.4 Hz); 2.63 (q,2H, J=7.6 Hz); 2.51 (qt, 2H, J=7.6 Hz); 1.24 (t, 3H, J=7.6 Hz).

b) 2-[4-(1,1-Dioxo-isothiazolidin-2-yl)-2-fluoro-phenoxy]-5-ethyl-phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine by2-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-isothiazolidine1,1-dioxide (0.10 mmol; 38 mg), the title compound was prepared in 76%yield (0.08 mmol; 28 mg) after purification by preparative TLC on silicagel (dichloromethane/methanol—95/5).

MS (ES) m/e 374 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.11 (dd, 1H, J₁=12.0 Hz, J₂=2.5 Hz); 7.03-6.96(m, 2H); 6.88 (s1, 1H); 6.70 (d, 1H, J=8.2 Hz); 6.63 (dd, 1H, J, =8.2Hz, J₂=1.8 Hz); 3.73 (t, 2H, J=6.6 Hz); 3.39 (t, 2H, J=7.4 Hz);2.61-2.50 (m, 4H); 1.21 (t, 3H, J=7.6 Hz).

EXAMPLE 44 ethyl[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]carbamatea) ethyl[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]carbamate

4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (0.19 mmol; 50 mg) in 1 mLTHF/NaHCO₃ sat. (1/1), at 0° C. were added ethylchloroformate (0.38mmol; 41 mg). The reaction was stirred overnight at room temperature.The mixture was hydrolysed with NH₄Cl sat. (4 mL) and extracted withdichloromethane (3*2 mL). Combined organic phases were dried overNa₂SO₄, concentrated in vacuo. The title compound (36 mg; 56%) wasobtained as a brown oil, after purification by preparative TLC on silicagel (ethyl acetate/cyclohexane—70/30).

MS (ES) m/e 334 (M+H)⁺

b) ethyl[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]carbamate

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine byethyl[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]carbamate (0.11 mmol;35 mg), the title compound was prepared in 69% yield (0.07 mmol; 23 mg)after purification by preparative TLC (ethyl acetate/cyclohexane—70/30).

MS (ES) m/e 320 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.41 (d, 1H, J=12.0 Hz); 6.99-6.96 (m, 2H); 6.88(s1, 1H); 6.67 (d, 1H, J=8.1 Hz); 6.62 (dd, 1H, J₁=8.2 Hz, J₂=1.8 Hz);4.23 (q, 2H, J=7.1 Hz); 2.58 (q, 2H, J=7.6 Hz); 1.31 (t, 3H, J=7.1 Hz);1.21 (t, 3H, J=7.6 Hz).

EXAMPLE 45 5-ethyl-2-[4-(ethylamino)-2-fluorophenoxy]phenol a)N-ethyl-4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for4-ethyl-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene (1.16 g; 4.0 mmol)and tetrahydrofurane for ethanol (16 mL), two compounds were obtainedafter purification on silica gel (gradient cyclohexane/dichloromethane)4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (466 mg; 45%)

MS (ES) m/e 262 (M+H)⁺

N-ethyl-4-(4-ethyl-2-methoxyphenox)-3-fluoroaniline (461 mg; 40%) MS(ES) m/e 290 (M+H)⁺

b) 5-ethyl-2-[4-(ethylamino)-2-fluorophenoxy]phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine forN-ethyl-4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (461 mg; 1.59mmol), the title compound (270 mg; 62%) was prepared as a light brownsolid, after purification by chromatography on silica gel (gradientdichloromethane/ethyl acetate).

MS (ES) m/e 276 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 6.93 (t, 1H, J=8.9 Hz); 6.87 (s, 1H); 6.62 (q,2H, J=6.6 Hz); 6.46 (dd, 1H, J₁=12.7 Hz, J₂=2.5 Hz); 6.37 (d, 1H, J=8.7Hz); 3.15 (q, 2H, J=7.2 Hz); 2.59 (q, 2H, J=7.6 Hz); 1.30 (t, 3H, J=7.1Hz); 1.21 (t, 3H, J=7.6 Hz).

EXAMPLE 46 5-ethyl-2-[2-(methylamino)phenoxy]phenol a)N-[2-(4-ethyl-2-methoxyphenoxy)phenyl]formamide

To acetic anhydride (0.53 mmol; 51 μL) under argon, at 0° C., was addedformic acid (0.66 mmol; 25 μL). The reaction was stirred 2 hours at 60°C. After cooling to 0° C., the mixture was diluted with 1 mL of dry THF,followed by a solution of 2-(4-ethyl-2-methoxyphenoxy)aniline (0.21mmol; 50 mg) in dry THF (1 mL). The reaction was stirred 2 hours at roomtemperature. The mixture was concentrated in vacuo to give the titlecompound (72 mg; quantitative) as a brown oil, used without furtherpurification.

MS (ES) m/e 272 (M+H)⁺.

b) 2-(4-ethyl-2-methoxyphenoxy)-N-methylaniline

To a solution of N-[2-(4-ethyl-2-methoxyphenoxy)phenyl]formamide (0.21mmol; 72 mg), under argon, in dry THF was added at 0° C., boranedimethylsulfide complex (0.51 mmol, 49 μL). The reaction was stirred atreflux for 3 h 30. After cooling to 0° C., the mixture was diluted with1 mL of dry methanol and stirred 1 hour. HCl (4M in dioxane) was addedat 0° C. until pH 2, then the mixture was refluxed 1 hour. After coolingto room temperature, the reaction was diluted with 5 mL of methanol andconcentrated in vacuo. The crude was treated with 5 mL of NaOH (1N),until pH 12, and extracted with ethyl acetate (3*2 mL). Combined organicphases were dried over Na₂SO₄ and concentrated in vacuo to yield thetitle compound (66 mg, quantitative) as a red oil used without furtherpurification.

MS (ES) m/e 258 (M+H)⁺.

c) 5-ethyl-2-[2-(methylamino)phenoxy]phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine by2-(4-ethyl-2-methoxyphenoxy)-N-methylaniline (0.26 mmol; 66 mg), thetitle compound was prepared in 50% yield (0.13 mmol; 31 mg) afterpurification by preparative TLC (ethyl acetate/cyclohexane—70/30).

MS (ES) m/e 244 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.07 (t, 1H, J=6.6 Hz); 6.88 (s, 1H); 6.81-6.76(m, 3H); 6.69-6.64 (m, 2H); 2.89 (s, 3H); 2.60 (q, 2H, J=7.6 Hz); 1.23(t, 3H, J=7.6 Hz).

EXAMPLE 47 5-ethyl-2-[4-(methylsulfonyl)phenoxy]phenol a)4-(4-ethyl-2-methoxyphenoxy)phenyl methyl sulfone

To a suspension of Cu(OAc)₂ (3.0 mmol; 543 mg),4-(methanesulphonyl)benzeneboronic acid (4.0 mmol; 800 mg) and activatedmolecular sieves (800 mg) under air, in anhydrous dichloromethane (5mL), were added 2-methoxy-4-ethylphenol (2.0 mmol; 0.28 mL), anhydroustriethylamine (10 mmol; 1.4 mL), and anhydrous pyridine (10 mmol; 0.8mL). The reaction was stirred for 2 days at room temperature. The crudewas filtered on silica gel, washed with ethyl acetate, concentrated. Theresidue was then purified by column chromatography (gradientcyclohexane/dichloromethane) to yield the title compound as clear oil(617 mg; 2.0 mmol; quantitative).

MS (ES) m/e 307 (M+H)⁺

b) 5-ethyl-2-[4-(methylsulfonyl)phenoxy]phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for4-(4-ethyl-2-methoxyphenoxy)phenyl methyl sulfone (130 mg; 0.42 mmol),the title compound (94 mg; 76%) was prepared as a white solid, afterpurification by preparative TLC (dichloromethane).

MS (ES) m/e 293 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.91 (d, 2H, J=8.8 Hz); 7.13 (d, 2H, J=8.9 Hz);6.95 (s, 1H) 6.92 (d, 1H, J=8.2 Hz); 6.78 (d, 1H, J=8.2 Hz); 3.07 (s,3H); 2.66 (q, 2H, J=7.6 Hz); 1.26 (t, 3H, J=7.6 Hz).

EXAMPLE 48 5-Ethyl-2-[2-fluoro-4-(3-hydroxy-propylamino)-phenoxy]-phenola) 2-(benzyloxy)-4-ethyl-1-(2-fluoro-4-nitrophenoxy)benzene

According to the procedure of example 20 (a) except substituting1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 3,4-difluoronitrobenzene(30.5 g; 192 mmol), and 2-methoxy-4-ethylphenol for2-(benzyloxy)-4-ethylphenol (33.6 g; 147 mmol) the title compound (58.1g; 100%) was prepared as a brown oil, used without further purification.

b) 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline

To a solution of 2-(benzyloxy)-4-ethyl-1-(2-fluoro-4-nitrophenoxy)benzene (25 g; 68 mmol) in ether (86 mL), under argon cooled to0° C., was added a suspension of tin dichloride (153 g; 801 mmol) in HCl(50 mL; 2 mol). The mixture was allowed to warm up to room temperatureovernight, then a 10% NaOH solution was added dropwise. The resultingmixture was extracted with ethyl acetate (5*400 mL). Combined organicphases were washed with water (400 mL) and brine, then dried over Na₂SO₄and concentrated. The residue was purified on silica gel (ethylacetate/cyclohexane 1:9) to yield the title compound as a light brownsolid (15.8 g; 68.8%)

MS (ES) m/e 338 (M+H)⁺

c) 3-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenylamino]-propan-1-ol

4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline (500 mg, 1.48 mmol),K₂CO₃ (1.23 g, 8.9 mmol) and 3-bromo-1-propanol (410 mg, 2.9 mmol) weretaken in dry DMF (2 ml) in a microwave vial and was subjected tomicrowave at 180° C. for 2 h. The reaction mixture was filtered overcelite and the residue washed thoroughly with ethyl acetate. Thecombined organic fractions including the filtrate were washed withwater, brine, dried over Na₂SO₄ and concentrated. The crude obtained wascombined with earlier crude products obtained from a 100 mg and 200 mgbatches and purified together by column chromatography over silica gelusing 40% ethylacetate in pet ether as eluant to get 400 mg (42.6%) ofpure title compound.

d) 5-Ethyl-2-[2-fluoro-4-(3-hydroxy-propylamino)-phenoxy]-phenol

3-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenylamino]-propan-1-ol(400 mg, 1.01 mmol) was taken in 15 ml of absolute ethanol, undernitrogen. To this was added Pd(OH)₂, (20%, 50 mg) followed by ammoniumformate (200 mg, 3.1 mmol). The reaction mixture was heated at 65° C.and monitored by TLC. After complete consumption of starting material(20 minutes), the heating was stopped and mixture cooled to rt. Thereaction mixture was filtered through celite and the residue was washedwith methanol. The combined filtrate was concentrated to obtain 300 mgof crude compound showing 70% by HPLC. The crude was purified bypreparative HPLC (Column: C18 Symmetry (300×19 mm), 7μ, Mobile phase A:20 mM ammonium acetate, Mobile phase B: Acetonitrile) to get 140 mg(45.3%) of title compound.

EXAMPLE 495-ethyl-2-(4-{[(E)-pyrrolidin-2-ylidenemethyl]sulfonyl}phenoxy)phenol a)(2E)-2-({[4-(4-ethyl-2-methoxyphenoxy)phenyl]sulfonyl}methylene)pyrrolidine

To a solution of 4-(4-ethyl-2-methoxyphenoxy)phenyl methyl sulfone (0.44mmol; 136 mg), in anhydrous THF (1 mL), under argon, cooled to 0° C.,was added sBuLi (1.2M in cyclohexane; 0.89 mmol; 0.74 mL). Afterstirring for 30 min, a solution of 1-BOC-2-Pyrrolidinone (0.44 mmol;0.08 mL) in anhydrous THF (1 mL) was slowly added. The reaction wasstirred at 0° C. for 30 min. then slowly warmed up to room temperatureovernight. The mixture was quenched with water and NH₄Cl sat. (3 mL),extracted with ethyl acetate (2*3 mL), to yield a light yellow oil (164mg), used without further purification.

MS (ES) m/e 374 (M+H)⁺

b) 5-ethyl-2-(4-{[(E)-pyrrolidin-2-ylidenemethyl]sulfonyl}phenoxy)phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for(2E)-2-({[4-(4-ethyl-2-methoxyphenoxy)phenyl]sulfonyl}methylene)pyrrolidine(164 mg; 0.44 mmol), the title compound (34 mg; 0.09 mmol; 22%) wasprepared as a clear oil, after purification by preparative TLC(dichloromethane/ethyl acetate).

MS (ES) m/e 378 (M+H₂O+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.78 (d, 2H, J=8.8 Hz); 6.99 (d, 2H, J=8.8 Hz);6.90 (s, 1H); 6.87 (d, 1H, J=8.3 Hz); 6.73 (d, 1H, J=8.0 Hz); 4.66 (s,1H); 3.75 (t, 2H, J=1.8 Hz); 2.79 (q, 2H, J=6.7 Hz); 2.63 (t, 2H, J=7.6Hz); 1.95 (qu, 2H, J=7.1 Hz); 1.24 (t, 3H, J=7.6 Hz).

EXAMPLE 50:2-(2-amino-5-fluorophenoxy)-5-ethylphenol a)4-ethyl-1-(3-fluoro-4-nitrophenoxy)-2-methoxybenzene and4-ethyl-1-(5-fluoro-2-nitrophenoxy)-2-methoxybenzene

According to the procedure of example 20 (a) except substituting1-fluoro-4-nitro-2-(trifluoromethyl)benzene for1,3-difluoro-4-nitrobenzene (110 μL; 1 mmol), the title products wereobtained as a yellow solid (253 mg; 87%), after purification bypreparative TLC (cyclohexane/ethyl acetate: 9/1).

MS (ES) m/e 292 (M+H)⁺

b) 4-(4-ethyl-2-methoxyphenoxy)-2-fluoroaniline and2-(4-ethyl-2-methoxyphenoxy)-4-fluoroaniline

To a solution of 4-ethyl-1-(3-fluoro-4-nitrophenoxy)-2-methoxybenzeneand 4-ethyl-1-(5-fluoro-2-nitrophenoxy)-2-methoxybenzene (100.5 mg, 0.69mmol) in ethanol (5 mL) was added Tin(II)chloride dihydrate (794 mg,3.45 mmol). The reaction mixture was heated to reflux for 1 h 30. Thereaction mixture was washed with water, solid sodium hydrogenocarbonateand a NaOH solution (1 N). The mixture was extracted with ethyl acetate.Combined organic phases were dried over Na₂SO₄, concentrated in vacuo,to give the title products as a light brown oil (51 mg; 28%), afterpurification by preparative TLC (cyclohexane/ethyl acetate: 7/3).

MS (ES) m/e 262 (M+H)⁺.

c) 2-(2-amino-5-fluorophenoxy)-5-ethylphenol

According to the procedure of example 5 (b), except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for a mixture of4-(4-ethyl-2-methoxyphenoxy)-2-fluoroaniline and2-(4-ethyl-2-methoxyphenoxy)-4-fluoroaniline (50.9 mg, 0.19 mmol), thetitle compound (8.9 mg; 19%) was obtained after purification bypreparative TLC (dichloromethane/ethyl acetate: 9/1).

MS (ES) m/e 248 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 6.90-6.87 (m, 2H); 6.80-6.67 (m, 3H); 6.59 (dd,1H, J₁=2.8 Hz; J₂=9.6 Hz); 2.62 (q, 2H, J=7.6 Hz); 1.25 (t, 3H, J=7.6Hz).

EXAMPLE 51N-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-2,2,2-trifluoroethanesulfonamidea)N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]-2,2,2-trifluoroethanesulfonamide

According to the procedure of example 42 (a) except substituting3-chloropropanesulfonyle chloride by

Trifluoroethanesulfonyl chloride (0.46 mmol; 84 mg), the title compoundwas prepared (177 mg; quantitative yield) as a brown oil used withoutfurther purification.

MS (ES) m/e 408 (M+H)⁺

b)N-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-2,2,2-trifluoroethanesulfonamide

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine byN-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]-2,2,2-trifluoroethanesulfonamide(0.38 mmol; 156 mg), the title compound was prepared in 53% yield (0.20mmol; 80 mg) after purification by preparative TLC (cyclohexane/ethylacetate-7/3).

MS (ES) m/e 394 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.19 (dd, 1H, J, =11.4 Hz, J₂=2.4 Hz); 7.11 (s1,1H); 7.01-6.93 (m, 2H); 6.90 (d, 1H, J=1.9 Hz); 6.77 (d, 1H, J=8.2 Hz);6.69 (dd, 1H, J, =8.2 Hz, J₂=2.0 Hz); 3.83 (q, 2H, J=8.8 Hz); 2.60 (q,2H, J=7.6 Hz); 1.24 (t, 3H, J=7.6 Hz).

EXAMPLE 52 N-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]cyclopropanesulfonamide a)N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]cyclopropane sulfonamide

According to the procedure of example 42 (a) except substituting3-chloropropanesulfonyle chloride by cyclopropanesulfonyl chloride (0.46mmol; 47 μL), the title compound was prepared (170 mg; quantitativeyield) as a brown oil used without further purification.

MS (ES) m/e 366 (M+H)⁺

b) N-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]cyclopropanesulfonamide

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine byN-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]cyclopropane sulfonamide(0.38 mmol; 140 mg), the title compound was prepared in 94% yield (0.36mmol; 126 mg) after purification by preparative TLC (cyclohexane/ethylacetate—7/3).

MS (ES) m/e 352 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.19 (d, 1H, J=11.8 Hz); 6.97 (m, 2H); 6.87 (m,2H); 6.72 (d, 1H, J=8.3 Hz); 6.66 (dd, 1H, J, =8.3 Hz, J₂=2.0 Hz); 2.59(q, 2H, J=7.6 Hz); 2.51 (m, 1H); 1.24-1.17 (m, 5H); 1.03-0.98 (m; 2H)

EXAMPLE 53 5-ethyl-2-{4-[(3-hydroxybutyl) sulfonyl]phenoxy}phenol a)4-{[4-(4-ethyl-2-methoxyphenoxy)phenyl]sulfonyl}butan-2-ol

According to the procedure of example 49(a) except substituting1-BOC-2-Pyrrolidinone for propylene oxide (0.2 mL; 2.8 mmol), the titlecompound (200 mg; 0.56 mmol; 100%) was prepared as a yellow oil, usedwithout purification.

MS (ES) m/e 365 (M+H)⁺

b) 5-ethyl-2-{4-[(3-hydroxybutyl)sulfonyl]phenoxy}phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for4-{[4-(4-ethyl-2-methoxyphenoxy)phenyl]sulfonyl}butan-2-ol (200 mg; 0.56mmol), the title compound (11 mg; 0.03 mmol; 6%) was prepared as a clearoil, after purification by preparative TLC (dichloromethane/ethylacetate).

MS (ES) m/e 351 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.81 (d, 2H, J=8.9 Hz); 7.08 (d, 2H, J=8.9 Hz);6.90 (d, 2H, J=9.9 Hz); 6.75 (d, 1H, J=8.2 Hz); 5.6 (s1, 1H); 3.90 (m,1H); 3.21 (m, 2H); 2.63 (q, 2H, J=7.6 Hz); 1.91 (m, 1H); 1.74 (m, 1H);1.26 (t, 3H, J=7.6 Hz); 1.20 (d, 3H, J=6.2 Hz).

EXAMPLE 54 2-(2-amino-5-methylphenoxy)-5-ethylphenol a)4-ethyl-2-methoxy-1-(5-methyl-2-nitrophenoxy)benzene

According to the procedure of example 20(a) except substituting1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 2-fluoro-4-nitrotoluene(157 mg; 1 mmol), the title compound (258 mg; 90%) was prepared as ayellow oil after purification by preparative TLC (cyclohexane/ethylacetate: 7/3).

MS (ES) m/e 288 (M+H)⁺.

b) 4-ethyl-2-methoxy-1-[(3-methyl-5-amino)phenoxy]benzene

According to the procedure of example 50(b) except substituting4-(4-ethyl-2-methoxyphenoxy)-2-fluoroaniline and2-(4-ethyl-2-methoxyphenoxy)-4-fluoroaniline for4-ethyl-2-methoxy-1-[(5-methyl-2-nitro)phenoxy]benzene (257 mg, 0.90mmol), the title compound was prepared as a brown oil (167 mg; 72%),after purification by preparative TLC (cyclohexane/ethyl acetate: 7/3).

MS (ES) m/e 258 (M+H)⁺.

c) 2-(2-amino-5-methylphenoxy)-5-ethylphenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for2-(4-ethyl-2-methoxyphenoxy)-4-methylaniline (66.4 mg, 0.26 mmol), thetitle compound was prepared as a brown solid (4.9 mg; 8%), afterpurification by preparative TLC (cyclohexane/ethyl acetate: 7/3).

MS (ES) m/e 244 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 6.89 (d, 1H, J=2 Hz); 6.83 (d, 1H, J=8 Hz); 6.79(d, 1H, J=8 Hz); 6.75 (d, 1H, J=8 Hz); 6.68 (s, 1H); 6.66 (d, 1H, J=2Hz); 2.61 (q, 2H, J=7.6 Hz); 2.21 (s, 3H); 1.24 (t, 3H, 1.24 Hz).

EXAMPLE 55 2-(2-Fluoropyridin-3yloxy)-5-propylphenol a)3-(2-Methoxy-4-propylphenoxy)-2-nitropyridine

According to the procedure of example 21 (a3) except substituting4-ethyl-2-methoxyphenol by 2-methoxy-4-propylphenol (1.93 g, 11.61mmol), the title compound was prepared in 86% yield (2.6 g) afterpurification on silica gel (eluant ethyl acetate/pet ether 15:85) as apale yellow liquid.

¹H NMR (CDCl₃), δ (ppm): 8.16 (d, J=4.4 Hz, 1H), 7.42 (dd, J=8.4 Hz,J=4.4 Hz, 1H), 7.23 (d, J=8.4 Hz 1H), 7.05 (d, J=7.8 Hz, 1H), 6.8-6.83(m, 2H), 3.74 (s, 3H), 2.61 (t, J=7.4 Hz, 2H), 1.62-1.7 (m, 2H), 0.97(t, J=7.4 Hz, 3H)

LC-MS m/z 289.1 (M+H)⁺

b) 3-(2-Methoxy-4-propylphenoxy)-2-aminopyridine

To a stirred solution of 3-(4-propyl-2-methoxyphenoxy)-2-nitropyridine(1.1 g, 3.8 mmol) in methanol (15 ml) was added anhydrous Ferricchloride (55 mg, 5% by wt) and activated charcoal (55 mg, 5% by wt). Theresulting mixture was heated to reflux and hydrazine hydrate (570 mg,11.45 mmol) was added dropwise. The reaction was allowed to stir underreflux condition overnight, then filtered through celite. The filtratewas concentrated under reduced pressure, taken in ethyl acetate (150ml). The organic layer was washed with water followed by brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was passed through silica column (eluant ethylacetate/petether 1:3 to get 900 mg (91.3%) of title compound as a pale yellowsolid.

¹H NMR (CDCl₃), δ (ppm): 7.74 (d, J=5.1 Hz, 1H), 6.9 (d, J=8 Hz, 1H),6.8-6.83 (m, 2H), 6.76 (d, J=8.12 Hz, 1H), 6.56 (dd, J=7.8 Hz, J=5.2 Hz,2H), 5.09 (bs, 2H), 3.82 (s, 3H), 2.59 (t, J=7.4 Hz, 2H), 1.60-1.66 (m,2H), 0.97 (t, J=7.3 Hz, 3H) LC-MS m/z 259.1 (M+H)⁺

c) 2-(2-Aminopyridin-3-yloxy)-5-propylphenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for3-(2-methoxy-4-propylphenoxy)pyridin-2-amine (0.9 g, 3.48 mmol), thetitle compound (0.52 g; 61%) was obtained.

¹H NMR (DMSO-d6), δ (ppm): 9.4 (s, D2O exchangeable, 1H), 7.59 (d, J=4.9Hz, 1H), 6.83 (d, J=8.08 Hz, 1H), 6.77 (d, J=1.6 Hz, 1H), 6.66-6.61 (m,2H), 6.43 (dd, J=7.6 Hz, J=4.88 Hz, 1H), 5.82 (bs, D2O exchangeable,2H), 2.46 (t, J=7.6 Hz, 2H), 1.58-1.52 (m, 2H), 0.88 (t, J=7.3 Hz, 3H)LC-MS m/z 244.8 (M+H)⁺

EXAMPLE 56N-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl]-4-morpholin-4-yl-4-oxo-butyramidea) 1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]pyrrolidine-2,5-dione

To 2-(4-aminophenoxy)-5-ethyl-4-fluorophenol (785 mg, 3 mmol) were addedtoluene (1.5 mL) and succinic anhydride (360.3 mg, 3.6 mmol). Thereaction was left to stir for 3 days at 110° C. under argon, thenconcentrated, dissolved in dichloromethane, washed with a saturatedsolution of NaHCO₂ and a solution of KOH (1 M) and extracted withdichloromethane. Combined organic phases were dried over Na₂SO₄,concentrated in vacuo, to give the title product as a white solid (624.3mg; 61%), after purification on silica gel (dichloromethane).

MS (ES) m/e 344 (M+H)⁺

b)N-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-4-morpholin-4-yl-4-oxo-butyramide

To 1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]pyrrolidine-2,5-dione(40.4 mg, 0.12 mmol) were added acetonitrile (120 μL) and morpholine (20μL, 0.24 mmol). The reaction mixture was stirred at 30° C. for 3 daysunder argon, then concentrated, dissolved in ethyl acetate, washed withsaturated NH₄Cl and extracted with ethyl acetate. Combined organicphases were dried over Na₂SO₄, concentrated in vacuo, to give the titleproduct (45.1 mg; 87%) after purification by preparative TLC(dichloromethane/methanol: 9/1).

MS (ES) m/e 431 (M+H)⁺

c)N-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl]-4-morpholin-4-yl-4-oxo-butyramide

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine forN-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-4-morpholin-4-yl-4-oxo-butyramide(45 mg, 0.10 mmol), the title compound was prepared as a white solid (29mg; 69%), after purification by preparative TLC(dichloromethane/methanol: 95/5).

MS (ES) m/e 417 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 7.64 (dd, 1H, J, =2.4 Hz, J₂=12.4 Hz); 7.10-7.07(m, 1H); 6.97 (t, 1H, J=8.8 Hz); 6.89 (d, 1H, J=1.6 Hz); 6.68 (d, 1H,J=8.0 Hz); 6.63 (dd, 1H, J, =2 Hz, J₂=8.4 Hz), 3.73-3.66 (m, 8H),2.76-2.73 (m, 4H), 2.60 (q, 2H, J=1.6 Hz), 1.23 (t, 3H, J=1.6 Hz).

EXAMPLE 57 2-fluoro-6-[(3-fluoro-4-ethyl-6-hydroxy)phenoxy)]pyridine a)2-(4-bromo-5-fluoro-2-methoxyphenoxy)-6-fluoropyridine

According to the procedure of example 20(a) except substituting2-methoxy-4-propylphenol for 4-bromo-5-fluoro-2-methoxyphenol (441 mg; 2mmol), and 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for2,6-Difluoropyridine (0.18 mL; 2 mmol), the title compound was preparedas a yellow oil (246 mg; 39%), after purification on silica gel(cyclohexane/ethyl acetate: 95/5).

MS (ES) m/e 317 (M+H)⁺.

b) 2-fluoro-6-(5-fluoro-2-methoxy-4-vinylphenoxy)pyridine

To 2-(4-bromo-5-fluoro-2-methoxyphenoxy)-6-fluoropyridine (227 mg, 0.71mmol) were added[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (58.9 mg, 0.07 mmol) and potassium carbonate (597 mg,4.26 mmol). To the mixture were added acetonitrile (4 mL), water (1.3mL) and vinyl boronic acid pinacol ester (180 μL, 1.07 mmol). Thereaction was flushed with argon, and left to stir for 3 days at 60° C.The reaction mixture was then filtered on celite, rinsed withdichloromethane and concentrated. After purification by preparative TLC(cyclohexane/ethyl acetate: 70/30), the title product was isolated as anorange oil (166 mg, 89%).

MS (ES) m/e 264 (M+H)⁺.

c) 2-fluoro-6-[(3-fluoro-4-ethyl-6-methoxy)phenoxy)]pyridine

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for2-fluoro-6-[(3-fluoro-4-vinyl-6-methoxy)phenoxy)]pyridine (166 mg; 0.63mmol) and tetrahydrofurane for ethanol (2 mL), the title product wasisolated (145.4 mg, 87%) after purification by preparative TLC(cyclohexane/ethyl acetate: 80/20).

MS (ES) m/e 266 (M+H)⁺.

d) 2-fluoro-6-[(3-fluoro-4-ethyl-6-hydroxy)phenoxy)]pyridine

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for2-fluoro-6-[(3-fluoro-4-ethyl-6-methoxy)phenoxy)]pyridine (145 mg, 0.55mmol), the title compound (120.5 mg; 87%) was prepared as an oil, afterpurification by preparative TLC (cyclohexane/ethyl acetate: 7/3).

MS (ES) m/e 252 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 7.83 (q, 1H, J=8 Hz); 6.92 (d, 1H, J=7.6 Hz);6.84 (d, 2H, J=9.6 Hz); 6.70 (dd, 1H, J=8 Hz); 2.65 (q, 2H, J=7.6 Hz);1.26 (t, 3H, J=3.6 Hz).

EXAMPLE 582-(4-{[2-(1,3-dioxolan-2-yl)ethyl]sulfonyl}phenoxy)-5-ethylphenol a)2-{2-[4-(4-Ethyl-2-methoxy-phenoxy)-benzenesulfonyl]-ethyl}-[1,3]dioxolane

According to the procedure of example 49(a) except substituting1-BOC-2-Pyrrolidinone for 2-Bromomethyl-1,3-dioxolane (0.05 mL; 0.47mmol), the title compound (152 mg; 0.39 mmol; 100%) was prepared as ayellow oil, used without purification.

MS (ES) m/e 393 (M+H)⁺

b) 2-(4-{[2-(1,3-dioxolan-2-yl)ethyl]sulfonyl}phenoxy)-5-ethylphenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for2-{2-[4-(4-Ethyl-2-methoxy-phenoxy)-benzenesulfonyl]-ethyl}-[1,3]dioxolane (152 mg; 0.39 mmol), the title compound(3 mg; 0.02 mmol; 2%) was prepared as a clear oil, after purification bypreparative TLC (dichloromethane/ethyl acetate).

MS (ES) m/e 379 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.86 (d, 2H, J=8.8 Hz); 7.12 (d, 2H, J=8.8 Hz);6.95 (d, 1H, J=1.7 Hz); 6.92 (d, 1H, J=8.2 Hz); 6.78 (d, 1H, J=8.2 Hz);4.97 (t, 1H, J=3.9 Hz); 3.94 (m, 2H); 3.85 (m, 2H); 3.23 (m, 2H); 2.66(q, 2H, J=7.6 Hz); 2.10 (m, 2H); 1.26 (t, 3H, J=7.6 Hz).

EXAMPLE 59 (5R)-3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one a)[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenyl]-carbamic acid benzylester

According to the procedure of example 44 (a) except substituting4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline for4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline (200 mg; 0.59 mmol) andethylchloroformate by benzylchloroformate (150 μL; 0.73 mmol), the titlecompound (300 mg; quantitative) was prepared as a brown solid and usedwithout further purification.

MS (ES) m/e 494 (M+Na)⁺

b)(5R)-3-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenyl]-5-hydroxymethyl-oxazolidin-2-one

To a solution of[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenyl]-carbamic acid benzylester (0.31 mmol; 145 mg), under argon, in dry THF cooled to −78° C.,was added n-Butyl lithium 2.3M in THF (0.46 mmol; 200 μL). the reactionmixture was stirred ten minutes and (R)-glycidyl butyrate (0.34 mmol; 48μL) was added. The reaction was stirred overnight with slow warming toroom temperature. The mixture was treated with saturated NH₄Cl andextracted with ethyl acetate. Combined organic phases were dried overNa₂SO₄ and concentrated in vacuo. The title compound (70 mg; 52%) wasobtained as . . . after purification by preparative TLC (eluant:dichloromethane/methanol: 95/5).

MS (ES) m/e 438 (M+H)⁺

c)(5R)-3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-5-(hydroxylmethyl)-1,3-oxazolidin-2-one

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for(5R)-3-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenyl]-5-hydroxymethyl-oxazolidin-2-one(0.16 mmol; 70 mg), the title compound (0.12 mmol; 41 mg; 73%) wasobtained as a white solid after purification by preparative TLC(dichloromethane/methanol: 9/1).

MS (ES) m/e 438 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.55 (dd, 1H, J, =12.6 Hz, J₂=2.6 Hz); 7.10-7.07(m, 1H); 6.98 (t, 1H, J=8.9 Hz); 6.88 (d, 1H, J=1.6 Hz); 6.68 (d, 1H,J=6.7 Hz); 6.63 (dd, 1H, J, =8.3 Hz, J₂=1.7 Hz); 4.74 (m, 1H); 4.02-3.96(m, 3H); 3.75 (dd, 1H, J₁=12.7 Hz, J₂=3.7 Hz); 2.58 (q, 2H, J=7.6 Hz);1.21 (t, 3H, J=7.6 Hz).

EXAMPLE 605-Aminomethyl-3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]oxazolidin-2-onea)3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one

According to the procedure of example 59 (b) except substituting(R)-glycidyl butyrate for (R,S)-glycidyl butyrate (0.43 mmol; 60 μL),the title compound (240 mg; quantitative) was prepared and used withoutfurther purification.

MS (ES) m/e 438 (M+Na)⁺

b) Methanesulfonic acid3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethylester

To a solution of 3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (240 mg, 0.54 mmol) in 5 ml ofdry dichloromethane and 0.16 ml (1.1 mmol) of triethylamine, cooled to0° C., was added a solution of methanesulfonyl chloride (0.06 ml, 0.76mmol) in 0.5 ml of dichloromethane dropwise. The reaction was allowed towarm to rt overnight. The reaction mixture was diluted with 20 ml water,20 ml of dichloromethane were added and the layers separated. Theaqueous layer was extracted with dichloromethane and the combineddichloromethane fraction was dried over anhydrous Na₂SO₄ andconcentrated. The crude residue obtained was column purified over silicagel using 20% ethyl acetate in petroleum ether as eluant to get 120 mg,42.8% of the title compound.

LC-MS m/z 516.1 (M+H)⁺

c)5-Azidomethyl-3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-oxazolidin-2-one

To a solution of methanesulfonic acid3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethylester (120 mg, 0.23 mmol) in 2 ml of dry DMF under nitrogen was addedsodium azide (57 mg, 0.88 mmol). The reaction mixture was stirred at 75°C. overnight. The reaction mixture was diluted with 15 ml water andextracted with ethyl acetate. The combined organic phase was washed withwater, saturated brine solution, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to get 100 mg of the title compound which was usedas such for the next step.

d) 5-Aminomethyl-3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]oxazolidin-2-one

To a solution of5-Azidomethyl-3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-oxazolidin-2-one (100 mg, 0.16 mmol), in 15 ml of ethyl acetate,under nitrogen, was added palladium (10% Pd/C, 10 mg) and the mixturewas stirred at rt under hydrogen overnight. The reaction mixture wasfiltered through celite and the residue was washed thoroughly with ethylacetate. The combined filtrate was concentrated and the obtained crudecompound was column purified over silica gel using a mixture of 5%methanol in chloroform as eluant to obtain 70 mg 74.4% of the reducedproduct5-Aminomethyl-3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-oxazolidin-2-one.Debenzylation of this 70 mg was achieved by repeating the reaction usingmethanol as solvent, to obtain 30 mg, 54.1% of the title compound.

¹H NMR (CD₃OD), δ (ppm): 7.64 (dd, J=13.12, J=2.6 Hz, 1H), 7.17-7.14 (m,1H), 6.87 (t, J=9 Hz, 1H), 6.8 (d, J=1.96 Hz, 1H), 6.74 (d, J=8.16 Hz,1H), 6.64 (dd, J=8.16 Hz, J=1.88 Hz, 1H), 4.74-4.70 (m, 1H), 4.12 (t,J=8.96 Hz, 1H), 3.82 (dd, J=8.96 Hz, J=6.8 Hz, 1H), 2.99-2.92 (m, 2H),2.57 (q, J=7.6 Hz, 2H), 1.22 (t, J=7.6 Hz, 3H)

LC-MS m/z 347.1 (M+H)⁺

EXAMPLE 61 N-{3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

To a solution of5-Aminomethyl-3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-oxazolidin-2-one(10 mg, 0.028 mmol) in 2 ml of dry dichloromethane, cooled to 0° C., wasadded acetic anhydride (3 mg, 0.028 mmol) taken in 0.2 ml ofdichloromethane. The reaction mixture was warmed to rt and stirred for 5minutes until reaction was complete on TLC. The reaction mixture wasdiluted with 3 ml of water and the layers separated. The aqueous layerwas extracted with dichloromethane and the combined organic fraction wasdried over anhydrous Na₂SO₄ and concentrated. The crude residue obtainedwas purified by preparative HPLC (Column: C18 Symmetry (300×19 mm), 7μ,Mobile phase A: 20 mM ammonium acetate, Mobile phase B: Acetonitrile) toget 6 mg, 55.2% of the title compound.

¹H NMR (CDCl₃), δ (ppm): 7.58 (d, J=12.4, 1H), 7.09-7.02 (m, 2H), 6.9(s, 1H), 6.71-6.64 (m, 2H), 6.15 (bs, 1H), 4.79 (bs, 1H), 4.04 (t, J=8.1Hz, 1H), 3.80-3.62 (m, 3H), 2.57 (q, J=7.6 Hz, 2H), 2.25 (s, 3H), 1.22(t, J=7.6 Hz, 3H) LC-MS m/z 389.2 (M+H)⁺

EXAMPLE 62 2-(4-aminophenoxy)-5-ethyl-4-fluorophenol a)4-[(3-fluoro-4-bromo-6-methoxy)phenoxy)]nitrobenzene

According to the procedure of example 20(a) except substituting1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 4-fluoronitrobenzene(210 μL; 2 mmol) and 2-methoxy-4-ethylphenol for4-bromo-5-fluoro-2-methoxyphenol (444 mg; 2 mmol), the title compound(527 mg; 77%) was prepared as a light yellow solid after purification onsilica gel (cyclohexane/ethyl acetate: 95/5).

b) 4-[(3-fluoro-4-vinyl-6-methoxy)phenoxy)]nitrobenzene

According to the procedure of example 57(b) except substituting2-(4-bromo-5-fluoro-2-methoxyphenoxy)-6-fluoro pyridine for4-[(3-fluoro-4-bromo-6-methoxy)phenoxy)]nitrobenzene (200.3 mg, 0.58mmol), the title product was isolated as an orange oil (129.7 mg, 77%)after purification by preparative TLC (cyclohexane/ethyl acetate:70/30).

MS (ES) m/e 290 (M+H)⁺.

c) 4-(4-ethyl-5-fluoro-2-methoxyphenoxy) aniline

According to the procedure of example 20(b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for4-[(3-fluoro-4-vinyl-6-methoxy) phenoxy)]nitrobenzene (129 mg; 0.44mmol) and tetrahydrofurane for ethanol (3 mL), the title compound wasisolated as an oil (45 mg, 39%) after purification by preparative TLC(cyclohexane/ethyl acetate: 70/30).

MS (ES) m/e 262 (M+H)⁺.

d) 2-(4-aminophenoxy)-5-ethyl-4-fluorophenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for4-(4-ethyl-5-fluoro-2-methoxyphenoxy)aniline (44 mg, 0.17 mmol), thetitle compound (7.9 mg; 19%) was prepared as a brown powder, afterpurification by preparative TLC (cyclohexane/ethyl acetate: 7/3).

MS (ES) m/e 248 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 6.89 (d, 2H, J=8.8 Hz); 6.84 (d, 1H, J=7.2 Hz);6.70 (d, 2H, J=9.2 Hz); 6.55 (d, 1H, J=10.4 Hz); 2.60 (q, 2H, J=7.6 Hz);1.21 (t, 3H, J=7.6 Hz).

EXAMPLE 63 2-(4-amino-2-fluorophenoxy)-5-[2-(3-thienyl)ethyl]phenol a)4-bromo-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene

According to the procedure of example 21 (a3) except substituting4-Ethyl-2-methoxy phenol by 4-bromogualacol (2.51 mmol; 510 mg) and3-Fluoro-2-nitropyridine by 3,4-difluoronitrobenzene (2.76 mmol; 305μL), the title compound was prepared as a clear oil in quantitativeyield (855 mg) and used without further purification.

b) 4-(4-bromo-2-methoxyphenoxy)-3-fluoroaniline

According to the procedure of example 50(b) except substituting4-ethyl-1-(3-fluoro-4-nitrophenoxy)-2-methoxybenzene and4-ethyl-1-(5-fluoro-2-nitrophenoxy)-2-methoxy benzene for4-bromo-1-(2-fluoro-4-nitrophenoxy)-2-methoxy benzene (1.88 mmol; 644mg), the title compound (87%, 512 mg) was obtained as a red oil, andused without further purification.

MS (ES) m/e 312, 314 (M+H)⁺

c) 2-(4-amino-2-fluorophenoxy)-5-bromophenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for4-(4-bromo-2-methoxyphenoxy)-3-fluoroaniline (1.64 mmol; 512 mg), thedesired compound was prepared as a dark solid in 72% yield (350 mg) andused without further purification.

MS (ES) m/e 297, 299 (M+H⁺)

d) O,N,N-triBoc-2-(4-amino-2-fluorophenoxy)-5-bromophenol

To a solution of 2-(4-amino-2-fluorophenoxy)-5-bromophenol (0.62 mmol;185 mg) in dry dichloromethane (3 mL), under argon, were added to 0° C.diisopropylethylamine (2.01 mmol; 350 μL) and (Boc)₂O (2.01 mmol, 439mg). The reaction was stirred with a gradual warming to roomtemperature. The mixture was treated with saturated NH₄Cl and extractedwith dichloromethane. Combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo to give a brown oil (quantitative, 363 mg) usedwithout further purification.

MS (ES) m/e 620, 622 (M+Na⁺)

e) O,N-diBoc-2-(4-amino-2-fluorophenoxy)-5-(3-thienyl ethynyl)phenol

According to the procedure of example 11 (a) except substituting5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine byO,N,N-triBoc-2-(4-amino-2-fluorophenoxy)-5-bromophenol (0.62 mmol; 363mg) and 3-butyn-1-ol by 3-ethynylthiophene (1.55 mmol; 153 μL), thetitle compound was obtained as a yellow solid (60%, 195 mg) afterpurification on silica gel (cyclohexane/ethyl acetate gradient).

MS (ES) m/e 548 (M+Na)⁺

f) O,N-diBoc-2-(4-amino-2-fluorophenoxy)-5-[2-(3-thienyl)ethyl]phenolandO,N-diBoc-2-(4-amino-2-fluorophenoxy)-5-[(E)-2-(3-thienyl)vinyl]phenol

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene forO,N,N-triBoc-2-(4-amino-2-fluorophenoxy)-5-bromophenol (0.37 mmol; 195mg) and THF by ethanol, a mixture of title compounds (167 mg; ≈80%) wasobtained as a yellow oil, used without further purification.

MS (ES) m/e 550, 552 (M+H)⁺

g) 2-(4-amino-2-fluorophenoxy)-5-[2-(3-thienyl)ethyl]phenol and2-(4-amino-2-fluorophenoxy)-5-[(E)-2-(3-thienyl)vinyl]phenol

To a mixture ofO,N-diBoc-2-(4-amino-2-fluorophenoxy)-5-[2-(3-thienyl)ethyl]phenol andO,N-diBoc-2-(4-amino-2-fluorophenoxy)-5-[(E)-2-(3-thienyl)vinyl]phenol(0.31 mmol; 162 mg) in dry THF (2 mL), cooled to 0° C. under argon, wasadded TFA (13 mmol, 1 mL). The reaction was stirred overnight withgradual warming to rt. The mixture was treated with saturated NaHCO₃ andextracted with ethyl acetate. Combined organic layers were dried andconcentrated in vacuo, the title mixture was obtained (44 mg, ≈43%) as awhite solid after purification on preparative TLC. MS (ES) m/e 328, 330(M+H)⁺

h) 2-(4-amino-2-fluorophenoxy)-5-[2-(3-thienyl)ethyl]phenol

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene by amixture of 2-(4-amino-2-fluorophenoxy)-5-[2-(3-thienyl)ethyl]phenol and2-(4-amino-2-fluorophenoxy)-5-[(E)-2-(3-thienyl)vinyl]phenol (0.13 mmol;44 mg), and THF by ethanol, the title compound was prepared in 14% yield(0.02 mmol; 6 mg) as a brown oil after purification by preparative TLC(cyclohexane/ethyl acetate—7/3).

MS (ES) m/e 330 (M+H)⁺

¹H RMN (MeOD) δ (ppm): 7.27 (dd, 1H, J₁=4.9 Hz, J₂=3.0 Hz); 6.98 (m,1H); 6.93 (dd, 1H, J, =4.9 Hz, J₂=1.2 Hz); 6.79 (t, 1H, J=8.9 Hz); 6.73(d, 1H, J=1.3 Hz); 6.57-6.52 (m, 3H); 6.46 (ddd, 1H, J, =8.6 Hz, J₂=2.6Hz, J₃=1.2 Hz); 2.91-2.87 (m, 2H); 2.82-2.78 (m, 2H).

EXAMPLE 64 5-ethyl-2-[2-fluoro-4-(methylsulfonyl)phenoxy]phenol a)4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl methyl sulfone

According to the procedure of example 20(a) except substituting1-fluoro-4-nitro-2-(trifluoromethyl)benzene for1,2-difluoro-4-(methylsulphonyl)benzene (310 mg; 1.6 mmol), the titlecompound (581 mg; 100%) was prepared as a light brown solid, usedwithout further purification.

MS (ES) m/e 325 (M+H)⁺.

b) 5-ethyl-2-[2-fluoro-4-(methylsulfonyl)phenoxy]phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl methyl sulfone (63 mg; 0.19mmol), the title compound (38 mg; 0.12%) was prepared as a clear oil,after purification by preparative. TLC (dichloromethane/ethyl acetate).

MS (ES) m/e 311 (M+H)⁺

¹H RMN (CDCl₃) δ (Ppm): 7.73 (dd, 1H, J₁=9.7 Hz, J₂=2.1 Hz); 7.61 (d,1H, J=8.6 Hz); 7.03 (t, 1H, J=8.5 Hz); 6.94 (s, 1H); 6.89 (d, 1H, J=8.2Hz); 6.77 (dd, 1H, J, =8.2 Hz; J₂=2.0 Hz); 5.65 (s1, 1H); 3.07 (s, 3H);2.64 (q, 2H, J=7.6 Hz); 1.25 (t, 3H, J=7.6 Hz).

EXAMPLE 65 4-(4-ethyl-2-hydroxyphenoxy)-3-fluorobenzene sulfonamide a)4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzenesulfonyl chloride

NaNO₂ (1.5 mmol; 103 mg) was slowly added to a solution of4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (1.0 mmol; 261 mg) inacetonitrile (8 mL), AcOH (0.8 mL), and conc. HCl (0.5 mL), under argonat 0° C., in the dark. After 30 min. stirring, this solution was slowlyadded to a solution of H₂SO₃ (50 mmol; 4 mL), and NaCl (10 mmol; 580 mg)cooled to 0° C. CuCl₂ (2 mmol; 268 mg) was slowly added. The reactionwas stirred with slow warming to room temperature for 3 hr, then heatedto 50° C. for 30 min. Cooled to 0° C., the mixture was slowly hydrolysedwith conc NH₃, extracted with dichloromethane (3*5 mL). Combined organicphases were dried over Na₂SO₄, concentrated, to yield a brown oil (344mg; 1.0 mmol; quantitative), used as such in the following reactions.

MS (ES) m/e 341 (M−Cl+MeOH)

b) 4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzenesulfonamide

Conc. NH₃ (5.0 mmol; 0.28 mL) was slowly added to a solution of4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzenesulfonyl chloride (1.0 mmol;344 mg) in THF (5 mL), under argon at 0° C. The reaction was stirredovernight with slow warming to room temperature. Diluted with ethylacetate (5 mL), the mixture was washed with HCl (1N), and sat. NH₄Cl.The organic phase was dried over MgSO₄, concentrated. The residue waspurified by chromatography (dichloromethane/ethyl acetate gradient) toyield the title compound as an off-white solid (108 mg; 0.33 mmol; 33%).

MS (ES) m/e 326 (M+H)⁺

c) 4-(4-ethyl-2-hydroxyphenoxy)-3-fluorobenzenesulfonamide

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for4-(4-ethyl-2-hydroxyphenoxy)-3-fluorobenzene sulfonamide (108 mg; 0.33mmol), the title compound (18 mg; 0.06 mmol; 18%) was obtained as awhite solid, after purification by preparative TLC(dichloromethane/ethyl acetate).

MS (ES) m/e 311 (M+H)⁺

¹H RMN (MeOD) δ (ppm): 7.76 (dd, 1H, J, =10.5 Hz, J₂=2.0 Hz); 7.61 (d,1H, J=8.6 Hz); 6.96 (d, 1H, J=8.2 Hz); 6.90-6.86 (m, 2H); 6.77 (d, 1H,J=8.2 Hz); 2.66 (q, 2H, J=7.6 Hz); 1.29 (t, 3H, J=7.6 Hz).

EXAMPLE 665-ethyl-2-{2-fluoro-4-[(pyridin-3-ylmethyl)amino]phenoxy}phenol a)4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(pyridin-3-yl methyl)aniline

To 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (261.2 mg, 1 mmol) wereadded methanol (4 mL) and nicotinaldehyde (120 μL, 1.2 mmol). Thereaction was stirred at 30° C. for 17 h under argon. To the reactionmixture was added NaBH₄ (38 mg, 1 mmol). The reaction was stirred at 30°C. for 4 h under argon. The resulting mixture was concentrated in vacuo,dissolved in dichloromethane, washed with a saturated solution of NH₄Cland extracted with dichloromethane. Combined organic phases were driedover Na₂SO₄, concentrated in vacuo, to give the title product as ayellow oil (160.5 mg; 46%), after purification by preparative TLC(cyclohexane/ethyl acetate: 7/3).

MS (ES) m/e 353 (M+H)⁺

b) 5-ethyl-2-{2-fluoro-4-[(pyridin-3-ylmethyl)amino]phenoxy}phenol

According to the procedure of example 5(b) except substituting2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(pyridin-3-ylmethyl)aniline(63.5 mg, 0.18 mmol), the title product as a brown solid (9.5 mg; 12%),after purification by preparative TLC (dichloromethane/methanol: 9/1).

MS (ES) m/e 339 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 8.65 (s, 1H); 8.57 (d, 1H, J—4 Hz); 7.53 (d, 1H,J=8 Hz); 7.32 (m, 1H); 6.95 (t, 1H, J=8 Hz); 6.87 (s, 1H); 6.62 (m, 2H);6.45 (dd; 1H; J₁=12.4 Hz, J₂=2.8 Hz); 6.37 (dd, 1H, J₁=12 Hz, J₂=4 Hz);4.36 (s, 2H); 2.58 (q, 2H, 7.6 Hz); 1.22 (t, 3H, J=7.6 Hz).

EXAMPLE 67 4-(4-ethyl-2-hydroxyphenoxy)-3-fluoro-N-(2-hydroxyethyl)benzenesulfonamide a)4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(2-methoxyethyl)benzenesulfonamide

According to the procedure of example 65(b) except substituting NH₃ for2-Methoxyethylamine (0.33 mL; 3.8 mmol), the title compound (118 mg;0.30 mmol; 32%) was obtained as a yellow oil, after purification bychromatography (cyclohexane/dichloromethane gradient).

MS (ES) m/e 384 (M+H)⁺

b)4-(4-ethyl-2-hydroxyphenoxy)-3-fluoro-N-(2-hydroxyethyl)benzenesulfonamide

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(2-methoxyethyl)benzenesulfonamide (116 mg; 0.30 mmol), the title compound (45 mg;0.13 mmol; 42%) was obtained as a clear oil, after purification bypreparative TLC (dichloromethane/ethyl acetate).

MS (ES) m/e 356 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.63 (dd, 1H, J₁=10.0 Hz, J₂=2.0 Hz); 7.50 (d,1H, J=8.7 Hz); 6.94-6.87 (m, 3H); 6.73 (d, 1H, J 8.3 Hz); 5.64 (t, 1H,J=5.8 Hz); 3.64 (t, 2H, J=4.7 Hz); 3.05 (q, 2H, J=4.8 Hz); 2.61 (q, 2H,J=7.6 Hz); 1.24 (t, 3H, J=7.6 Hz).

EXAMPLE 685-ethyl-2-{2-fluoro-4-[(1H-imidazol-2-ylmethyl)amino]phenoxy}phenol a)4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(1H-imidazol-2-ylmethyl)aniline

According to the procedure of example 66(a) except substitutingnicotinaldehyde for 1H-imidazole-2-carboxaldehyde (119 mg, 1.2 mmol),the title compound was prepared as a light yellow solid (288.2 mg; 85%),after purification by preparative TLC (dichloromethane/methanol: 9/1).

MS (ES) m/e 342 (M+H)⁺

b) 5-ethyl-2-{2-fluoro-4-[(1H-imidazol-2-ylmethyl)amino]phenoxy}phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(1H-imidazol-2-ylmethyl)aniline(288 mg, 0.84 mmol), the title compound was prepared as a brown oil(72.3 mg; 26%), after purification by preparative TLC(dichloromethane/methanol: 9/1).

MS (ES) m/e 328 (M+H)⁺

¹H NMR (MeOD) δ (ppm): 7.04 (s, 2H); 6.87 (t, 1H, J=8.8 Hz); 6.79 (d,1H, J=1.2 Hz); 6.61-6.51 (m, 3H); 6.44 (dd, 1H, J₁=8.8 Hz, J₂=2.0 Hz);4.41 (s, 2H); 2.58 (q, 2H, 7.6 Hz); 1.24 (t, 3H, 7.6 Hz).

EXAMPLE 69N-{[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]sulfonyl}acetamide a)N-{[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]sulfonyl}acetamide

To a solution of 4-(4-ethyl-2-hydroxyphenoxy)-3-fluorobenzenesulfonamide(0.28 mmol; 90 mg) in anhydrous dichloromethane (1 mL), under argon wereadded EDAC (0.36 mmol; 69 mg), DMAP (0.31 mmol; 38 mg) and acetic acid(0.36 mmol; 0.02 mL). The reaction was stirred overnight at roomtemperature. Diluted with dichloromethane (3 mL), the mixture was washedwith HCl (1N; 3 mL). The organic phase was dried over MgSO₄,concentrated to yield the desired compound as a yellow foam (90 mg; 0.25mmol; 89%), used as such in the following reaction.

MS (ES) m/e 368 (M+H)⁺

b) N-{[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]sulfonyl}acetamide

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine forN-{[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]sulfonyl}acetamide (90mg; 0.25 mmol), the title compound (46 mg; 0.13 mmol; 52%) was obtainedas a clear oil, after purification by preparative TLC(dichloromethane/ethyl acetate).

MS (ES) m/e 354 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.81 (dd, 1H, J₁=9.9 Hz, J₂=2.0 Hz); 7.70 (d,1H, J=8.7 Hz); 6.96-6.86 (m, 3H); 6.75 (d, 1H, J=8.2 Hz); 2.62 (q, 2H,J=7.6 Hz); 2.06 (s, 3H); 1.25 (t, 3H, J=7.6 Hz).

EXAMPLE 70N-{2-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-benzenesulfonylamino]-ethyl}-acetamidea) N-{2-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-benzenesulfonylamino]-ethyl}-acetamide

N-Acetylethylenediamine (1.1 mmol; 0.10 mL) was slowly added to asolution of 4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzenesulfonylchloride (0.94 mmol; 325 mg) and TEA (2.8 mmol; 0.40 mL) in anhydrousTHF (5 mL), under argon at 0° C. The reaction was stirred overnight withprogressive warming to room temperature. Concentrated, the mixture waspurified by chromatography (dichloromethane/methanol/ammonia gradient)to yield the title compound as a yellow oil (142 mg; 0.35 mmol; 37%)used as such in the following reaction.

MS (ES) m/e 411 (M+H)⁺

b) N-{2-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-benzenesulfonylamino]-ethyl}-acetamide

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine forN-{2-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-benzenesulfonylamino]-ethyl}-acetamide (142 mg; 0.35 mmol), the title compound(44 mg; 0.11 mmol; 32%) was obtained as a clear oil, after purificationby preparative TLC (dichloromethane/methanol).

MS (ES) m/e 397 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.58 (dd, 1H, J₁=10.0 Hz, J₂=2.0 Hz); 7.44 (d,1H, J=8.7 Hz); 6.91-6.88 (m, 2H); 6.84 (t, 1H, J=8.2 Hz); 6.74-6.68 (m,2H); 6.10 (br, 1H); 3.23 (br, 2H); 2.98 (br, 2H); 2.59 (q, 2H, J=7.6Hz); 1.88 (s, 3H); 1.24 (t, 3H, J=7.6 Hz).

EXAMPLE 71 4-(4-ethyl-2-hydroxyphenoxy)-3-fluoro-N-propylbenzenesulfonamide a)4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorobenzenesulfonyl chloride

According to the procedure of example 65(a) except substituting4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline for4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline (1.3 g; 3.8 mmol), thetitle compound (1.51 g; 3.6 mmol; 95%) was obtained as a brown oil usedwithout purification in the following reaction.

MS (ES) m/e 417 (M−Cl+MeOH)⁺

b) 4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-propyl-benzenesulfonamide

According to the procedure of example 65(b) except substituting4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzene sulfonyl chloride for4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorobenzene sulfonyl chloride andNH₃ for propylamine (1.7 mmol; 0.14 mL), the title compound (140 mg;0.32 mmol; 41%) was obtained as a brown oil after purification onpreparative TLC (dichloromethane).

MS (ES) m/e 444 (M+H)⁺

c) 4-(4-ethyl-2-hydroxyphenoxy)-3-fluoro-N-propyl benzenesulfonamide

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-propyl-benzenesulfonamide(140 mg; 0.32 mmol) and tetrahydrofurane for ethanol (3 mL), the titlecompound (70 mg; 62%) was obtained as a clear oil, after purification onpreparative TLC (dichloromethane)

MS (ES) m/e 354 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.65 (dd, 1H, J₁=10.0 Hz, J₂=2.1 Hz); 7.54 (d,1H, J=9.5 Hz); 6.95 (t, 1H, J=8.5 Hz); 6.93 (d, 1H, J=1.9 Hz); 6.87 (d,1H, J=8.2 Hz); 6.75 (d, 1H, J=8.2 Hz); 5.84 (br, 1H); 4.92 (t, 2H, J=6.1Hz); 2.92 (q, 2H, J=6.5 Hz); 2.63 (q, 2H, J=7.6 Hz); 1.51 (se, 2H, J=7.2Hz); 1.24 (t, 3H, J=7.6 Hz); 0.88 (t, 3H, J=7.5 Hz).

EXAMPLE 72N-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-4-hydroxybutanamide a)N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]-4-hydroxybutanamide

To 1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]pyrrolidine-2,5-dione(169.8 mg, 0.49 mmol) was added methanol (2 mL). The reaction mixturewas stirred for 1 h 30 at room temperature under argon. Acetonitrile (2mL) and NaBH₄ (190.7 mg, 4.9 mmol) were added to the reaction. Thereaction mixture was stirred at 50° C. for 17 h. Then it wasconcentrated, dissolved in dichloromethane, washed with a saturatedsolution of NH₄Cl and extracted with dichloromethane. Combined organicphases were dried over Na₂SO₄, concentrated in vacuo, to give the titleproduct as a white solid used without further purification (169.5 mg;100%).

MS (ES) m/e 348 (M+H)⁺

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine forN-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]-4-hydroxybutanamide(47.9 mg, 0.14 mmol), the title compound was prepared as a colorless oil(16.5 mg; 35%), after purification by preparative TLC(dichloromethane/methanol: 9/1).

MS (ES) m/e 334 (M+H)⁺

¹H NMR (CD₃OD) δ (ppm): 7.68 (dd, 1H, J, =12.8 Hz, J₂=2.4 Hz); 7.19 (m,1H); 6.88 (m, 2H); 6.76 (d, 1H, J=8.0 Hz); 6.68 (dd, 1H, J₁=8.4 Hz,J₂=2.0 Hz); 3.68 (t, 2H, J=6.2 Hz); 2.62 (q, 2H, J=7.6 Hz), 2.51 (t, 2H,J=7.6 Hz), 1.96 (qt, 2H, J=6.8 Hz); 1.27 (t, 3H, 7.6 Hz).

EXAMPLE 73 4-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-butyricacid ethyl ester a)1-{4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenyl}ethanone

According to the procedure of example 21 (a3) except substituting4-Ethyl-2-methoxy phenol by 2-(benzyloxy)-4-ethylphenol (1.3 g, 5.7mmol) and 3-Fluoro-2-nitropyridine by 1-(3,4-difluorophenyl)ethanone(0.98 g, 6.27 mmol), the title compound was prepared as a clear oil in96% yield (2 g) and used without further purification.

LCMS m/z 365.0 (M+H)⁺

b) 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenyl acetate

To a solution of1-{4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenyl}ethanone (3 g, 8.24mmol) in dry dichloromethane (30 ml), was added PTSA (0.047 g, 0.247mmol). The reaction mixture was cooled in an ice bath and mCPBA (50%H2O)(2.84 g, 8.24 mmol) was added portionwise. The resulting mixture wasstirred at RT for 3 days, then concentrated at 35-40 C. The residue waspurified by column chromatography, (pet ether:EtOAC). The resultingsolid was dissolved in pet ether, filtered then concentrated the yieldthe title compound (1.6 g; 51%)

LCMS m/z 379.2 (M−H)−

c) 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenol

To a solution of 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenyl acetate(1.6 g, 4.2 mmol) in MeOH:H₂O (35 ml:35 ml), was added KOH (0.83 g, 14.8mmol). The mixture was heated at 65° C. for 4.5 hours, concentrated invacuo, then extracted with EtOAC (25 ml*2). Combined organic phases weredried over Na₂SO₄ and concentrated. The residue was purified by columnchromatography, (pet ether: EtOAC 95:5), to yield the title compound asa white solid (630 mg; 44%) LCMS m/z 336.9 (M−H)−

d) 4-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenoxy]-butyric acidethyl ester

To a solution of 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenol (0.30mmol; 100 mg) in dry acetone (2 mL), under argon, were added potassiumcarbonate (0.35 mmol; 49 mg), NaI (0.06 mmol; 9 mg) and ethylbromobutyrate (0.35 mmol; 51 μL). The reaction was stirred 14 hours at60° C. Water (100 μL) and tetrabutylammonium hydroxide (0.03 mmol; 8 mg)were added and the mixture was stirred 16 hours at 60° C. The reactionwas hydrolysed with NH₄Cl sat. (5 mL) and extracted with ethyl acetate(3*3 mL). Combined organic phases were dried over Na₂SO₄, concentratedin vacuo. The title compound (100 mg; 0.22 mmol; 75%) was obtained as ayellow oil, after purification by preparative TLC (cyclohexane/ethylacetate: 7/3).

MS (ES) m/e 475 (M+Na)⁺

e) 4-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxyl-butyric acid ethylester

According to the procedure of example 48(d) except substituting3-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenylamino]-propan-1-ol for4-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenoxy]-butyric acid ethylester (0.22 mmol; 100 mg) the title compound was prepared as a clear oil(58 mg; 72%), after purification by preparative TLC (Cyclohexane/Ethylacetate: 7/3)

MS (ES) m/e 363 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.00 (t, 1H, J=9.1 Hz); 6.87 (s, 1H); 6.74 (dd,1H, J, =12.1 Hz, J₂=2.8 Hz); 6.64-6.59 (m, 3H); 4.15 (q, 2H, J=7.1 Hz);3.98 (t, 2H, J=6.1 Hz); 2.57 (q, 2H, J=7.6 Hz); 2.51 (t, 2H, J=7.3 Hz);2.11 (qt, 2H, J=7.0 Hz); 1.27 (t, 3H, J=7.1 Hz); 1.21 (t, 3H, J=7.6 Hz).

EXAMPLE 74 4-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-butyricacid

To a solution of ethyl4-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-butyric acid ethylester (0.16 mmol; 58 mg), in a THF/water mixture (1/1; 1 mL) was addedlithium hydroxide (0.64 mmol; 15 mg). The reaction was heated 1 hour at60° C. After cooling to 0° C., the reaction was treated withconcentrated HCl, and extracted with ethyl acetate (3*2 mL). Combinatedorganic phases were dried over Na₂SO₄ and concentrated in vacuo. Thetitle compound (0.16 mmol; 54 mg; quantitative) was obtained as a clearoil, used without purification.

MS (ES) m/e 335 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.00 (t, 1H, J=9.7 Hz); 6.87 (s, 1H); 6.74 (dd,1H, J, =12.1 Hz, J₂=2.8 Hz); 6.64-6.59 (m, 3H); 3.99 (t, 2H, J=6.0 Hz);2.61-2.55 (m, 4H); 2.13 (qt, 2H, J=6.9 Hz); 1.23 (t, 3H, J=7.6 Hz).

EXAMPLE 754-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-N-(2-pyridin-2-yl-ethyl)-benzenesulfonamidea)4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(2-pyridin-2-yl-ethyl)-benzenesulfonamide

According to the procedure of example 70(a) except substitutingN-Acetylethylenediamine for 2-(2-Aminoethyl) pyridine (1.5 mmol; 0.18mL), the title compound (150 mg; 0.30 mmol; 24%) was obtained as ayellow oil after purification via chromatography (gradientdichloromethane/ethyl acetate).

MS (ES) m/e 507 (M+H)⁺

b)4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-N-(2-pyridin-2-yl-ethyl)-benzenesulfonamide

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(2-pyridin-2-yl-ethyl)-benzenesulfonamide (150 mg; 0.30 mmol) and tetrahydrofurane for ethanol (3 mL),the title compound (70 mg; 62%) was obtained as a clear oil, afterpurification via preparative TLC (dichloromethane/ethyl acetate).

MS (ES) m/e 417 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 8.41 (d, 1H, J=4.8 Hz); 7.62 (t, 1H, J=9.4 Hz);7.53 (d, 1H, J=10.0 Hz); 7.45 (d, 1H, J=8.7 Hz); 7.17-7.13 (m, 2H);6.91-6.85 (m, 3H); 6.73 (d, 1H, J=8.2 Hz); 6.14 (br, 1H); 3.32 (t, 2H,J=5.8 Hz); 2.94 (t, 2H, J=6.3 Hz); 2.62 (q, 2H, J=7.6 Hz); 1.23 (t, 3H,J=7.6 Hz)

EXAMPLE 764-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-N-(3-imidazol-1-yl-propyl)-benzenesulfonamidea)4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(3-imidazol-1-yl-propyl)-benzenesulfonamide

According to the procedure of example 70(a) except substitutingN-Acetylethylenediamine for 1-(3-Aminopropyl)imidazole (1.5 mmol; 0.18mL), the title compound (160 mg; 0.31 mmol; 25%) was obtained as a brownoil after purification by preparative TLC (dichloromethane/methanol).

MS (ES) m/e 510 (M+H)⁺

b)4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-N-(3-imidazol-1-yl-propyl)-benzenesulfonamide

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(3-imidazol-1-yl-propyl)-benzenesulfonamide(160 mg; 0.31 mmol) and tetrahydrofurane for ethanol (3 mL), the titlecompound (55 mg; 42%) was obtained as a clear oil, after purificationvia preparative TLC (dichloromethane/methanol/triethylamine)

MS (ES) m/e 420 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.52 (d, 1H, J, =10.0 Hz); 7.43 (d, 1H, J=8.7Hz); 7.23 (s, 1H); 6.96-6.92 (m, 3H); 6.83-6.80 (m, 2H); 6.72 (d, 1H,J=8.2 Hz); 3.97 (t, 2H, J=6.4 Hz); 2.81 (t, 2H, J=6.3 Hz); 2.61 (q, 2H,J=7.6 Hz); 1.94 (q, 2H, J=6.3 Hz); 1.23 (t, 3H, J=7.6 Hz)

EXAMPLE 775-ethyl-2-(2-fluoro-4-[(1H-imidazol-4-ylmethyl)amino]phenoxy)phenol a)4(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(1H-imidazol-4-yl methyl)aniline

According to the procedure of example 66(a) except substitutingnicotinaldehyde for 4(5)-imidazole carboxadehyde (115.27 mg, 1.2 mmol),the title compound was prepared as a colorless oil (300 mg; 88%), afterpurification by preparative TLC (dichloromethane/methanol: 95/5+1%NH4+).

MS (ES) m/e 342 (M+H)⁺

b) 5-ethyl-2-(2-fluoro-4-[(1H-imidazol-4-ylmethyl)amino]phenoxy)phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for4(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(1H-imidazol-4-ylmethyl)aniline(300 mg, 0.87 mmol), the title compound (101 mg, 35%) was prepared as awhite solid, after purification by preparative TLC and washing withdiethyl ether (dichloromethane/methanol: 95/5+1% NH4+).

MS (ES) m/e 328 (M+H)⁺

¹H NMR (MeOD) δ (ppm): 7.62 (s, 1H), 6.97 (s, 1H), 6.79 (t, 1H, J=9.0Hz), 6.71 (s, 1H), 6.51-6.50 (m, 3H), 6.42 (dd, 1H, J₁=8.8 Hz, J₂=3.8Hz), 4.20 (s, 2H), 2.51 (q, 2H, J=7.6 Hz), 1.16 (t, 3H, J=7.6 Hz)

EXAMPLE 782-[(6-fluoropyridin-2-yl)oxy]-5-[3-(1H-1,2,4-triazol-1-yl)propyl]phenola) 3-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}prop-2-yn-1-ol

According to the procedure of example 11 (a) except substituting5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine by2-(4-bromo-2-methoxyphenoxy)-6-fluoropyridine (0.98 mmol; 300 mg) and3-butyn-1-ol by propargylic alcohol (2.50 mmol; 150 μL), the titlecompound was obtained as a yellow solid (71%, 191 mg) after purificationon silica gel (cyclohexane/ethyl acetate gradient).

MS (ES) m/e 274 (M+H)⁺

b) 3-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}prop-2-yn-ol

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene by3-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}prop-2-yn-1-ol (0.33mmol; 90 mg) and THF by absolute ethanol, the title compound(quantitative, 102 mg) was obtained as a yellow oil, and used withoutfurther purification.

MS (ES) m/e 339 (M+H)⁺

c) 2-[4-(3-chloropropyl)-2-methoxyphenoxy]-6-fluoropyridine

To a solution of3-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}prop-2-yn-ol (0.37mmol; 102 mg) in dry dichloromethane (2 mL), under argon, cooled to −40°C., was added triethylamine (0.41 mmol; 56 μL) then methanesulfonylchloride (0.39 mmol; 30 μL). The reaction mixture was allowed to stirfor 6 hr, with gradual warming to room temperature. The reaction washydrolysed with saturated NH₄Cl, extracted with ethyl acetate. Combinedorganic phases were dried over Na₂SO₄, concentrated in vacuo. The titlecompound (185 mg; 47%) was obtained as a light oil, after purificationon preparative TLC (cyclohexane/ethyl acetate: 7/3).

MS (ES) m/e 296 (M+H)⁺

d)2-fluoro-6-{2-methoxy-4-[3-(1H-1,2,4-triazol-1-yl)propyl]phenoxy}pyridine

To a solution of2-[4-(3-chloropropyl)-2-methoxyphenoxy]-6-fluoropyridine (0.14 mmol) ina THF/DMF mixture (340 μL/170 μL), under argon, was added NaI (0.14mmol; 21 mg). The mixture was stirred 30 minutes at 50° C., beforeaddition of diisopropylethylamine (0.28 mmol, 36 mg) and 1,2,4-triazol(0.28 mmol; 19 mg). The reaction mixture was allowed to stir overnightat 50° C. After concentration, the reaction was hydrolysed withsaturated NH₄Cl (1 mL), extracted with AcOEt (2*1 mL). Combined organicphases were dried over Na₂SO₄, concentrated in vacuo. The title compound(15 mg; 33%) was obtained as a yellow oil after purification onpreparative TLC (dichloromethane/methanol: 9/1).

MS (ES) m/e 329 (M+H)⁺

e) 2-[(6-fluoropyridin-2-yl)oxy]-5-[3-(1H-1,2,4-triazol-1-yl)propyl]phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for2-fluoro-6-{2-methoxy-4-[3-(1H-1,2,4-triazol-1-yl)propyl]phenoxy}pyridine(0.05 mmol; 15 mg), the desired compound was prepared in 41% yield (6mg) after purification by preparative TLC (dichloromethane/methanol:9/1).

MS (ES) m/e 315 (M+H⁺) ¹H RMN (MeOD) δ (ppm): 8.48 (s, 1H); 8.02 (s,1H); 7.85 (q, 1H, J=8.1 Hz); 6.96 (d, 1H, J=8.1 Hz); 6.79 (d, 1H, J=1.9Hz); 6.73-6.69 (m, 2H); 6.66 (dd, 1H, J, =7.9 Hz, J₂=2.2 Hz); 4.23 (t,2H, J=7.0 Hz); 2.59 (t, 2H, J=7.6 Hz); 2.22 (qt, 2H, J=7.6 Hz).

EXAMPLE 79N-methanesulfonyl-N-1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]propan-1,3-diaminea) N¹-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine

To 4-(2-benzyloxy-4-ethylphenoxy)-3-fluoroaniline (500 mg, 1.48 mmol) in25 ml of ethanol was added 3-bromopropylphthalimide (440 mg, 1.64 mmol).The mixture was refluxed for 2 days. The reaction mixture was dilutedwith ethylacetate and washed with water, saturated brine solution, driedover anhydrous Na₂SO₄ and concentrated. The crude obtained was passedthrough a silica gel column using 15% ethylacetate in petroleum ether aseluant. The LCMS of the obtained mixture showed 53% mass of the coupledproduct. This was taken in 25 ml of ethanol and added 7 ml of hydrazinehydrate and refluxed overnight. Ethanol was removed in vacuo and added20% KOH solution (20 ml) to the residue. The aqueous fraction was thenextracted with dichlormethane and the combined dichloromethane fractionwas dried over anhydrous Na₂SO₄ and concentrated. The crude productobtained was purified by column chromatography using 5% methanol indichloromethane as eluant to obtain 110 mg (18.8% after 2 steps) of theN¹-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine.

LC-MS m/z 395.9 (M+H)⁺

b)N-Methanesulfonyl-N¹-[4-(2-benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine

To a solution ofN¹-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (90mg, 0.23 mmol) in 5 ml of dry dichloromethane and 0.08 ml (0.57 mmol) oftriethylamine, cooled to 0° C., was added mesyl chloride (26 mg, 0.23mmol) taken in 0.5 ml of dichloromethane dropwise. The reaction wasquenched after 5 minutes as the reaction was complete on TLC. Thereaction mixture was diluted with water and the layers separated. Theaqueous layer was extracted with dichloromethane and the combineddichloromethane fraction was washed with water, dried over anhydrousNa₂SO₄ and concentrated. The crude residue obtained was combined withthe crude obtained from an earlier 20 mg batch and column purified oversilica gel using 2% methanol in dichloromethane as eluant to get 90 mg,68.3% of title compound.

LC-MS m/z 473.2 (M+H)⁺

c)N-methanesulfonyl-N¹-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]propan-1,3-diamine

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene forN-Methanesulfonyl-N¹-[4-(2-benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine(90 mg, 0.19 mmol) and tetrahydrofurane for methanol (15 mL), the titlecompound (50 mg, 68%) was obtained as a brown liquid, after purificationon silica gel (dichloromethane/ethyl acetate: 8/2)

¹H NMR (CDCl₃), δ (ppm): 6.93 (t, J=8.9 Hz, 1H), 6.87 (s, 1H), 6.66-6.57(m, 3H), 6.49 (d, J=8.1 Hz, 1H), 4.78 (bs, 1H), 3.3-3.28 (m, 4H), 2.98(s, 3H), 2.57 (q, J=7.5 Hz, 2H), 1.92 (m, 2H), 1.21 (t, J=7.5 Hz, 3H)

LC-MS m/z 383 (M+H)⁺

EXAMPLE 80 N-acetyl-N¹-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]propan-1,3-diamine a)N-acetyl-N¹-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine

To a solution ofN¹-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (60mg, 0.15 mmol) in 10 ml of dry dichloromethane, cooled to 0° C., wasadded acetic anhydride (20 mg, 0.19 mmol) taken in 0.5 ml ofdichloromethane dropwise.

The reaction mixture was warmed to rt and stirred for 1 h until reactionwas complete on TLC. The reaction mixture was diluted with water and thelayers separated. The aqueous layer was extracted with dichloromethaneand the combined dichloromethane fraction was dried over anhydrousNa₂SO₄ and concentrated. The crude residue obtained was column purifiedover silica gel using 2% methanol in dichloromethane as eluant to get 50mg, 75.4% of title compound.

LC-MS m/z 438.1 (M+H)⁺

b)N-acetyl-N¹-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]propan-1,3-diamine

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene forN-acetyl-N¹-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine(70 mg, 0.16 mmol) and tetrahydrofurane for methanol (15 mL), the titlecompound (50 mg, 91%) was obtained as a brown liquid, after purificationon silica gel (dichloromethane/ethyl acetate: 5/5)

¹H NMR (CDCl₃), δ (ppm): 6.93 (t, J=8.9 Hz, 1H), 6.86 (d, J=1.6 Hz, 1H),6.64-6.58 (m, 2H), 6.46-6.42 (m, 1H), 6.36 (d, J=8.8 Hz, 1H), 5.64 (bs,2H), 3.42-3.37 (m, 2H), 3.15 (t, J=6.4 HZ, 2H), 2.57 (q, J=7.59 Hz, 2H),2.06 (s, 3H), 1.80 (qt, J 6.48 Hz, 2H), 1.21 (t, J=7.58 Hz, 3H) LC-MSm/z 347.2 (M+H)⁺

EXAMPLE 81 5-Ethyl-2-[2-fluoro-4-(2-hydroxyethylamino)-phenoxy]phenol a)3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]oxazolidin-2-one

A solution of [4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-carbamicacid-benzyl ester (500 mg, 1.06 mmol) in 5 ml tetrahydrofuran undernitrogen atmosphere was cooled to −78° C. To this added 2.8M n-butyllithium (0.075 g, 1.16 mmol) dropwise and the stirring at −78° C. for 1h. Condensed ethylene oxide (0.5 ml, 9.9 mmol) was then added dropwiseto the reaction mixture and warmed slowly to rt. The reaction wasstirred at rt overnight and then quenched with saturated ammoniumchloride solution. The aqueous phase was extracted with dichloromethaneand the combined organic phase was dried over anhydrous Na₂SO₄ andconcentrated. The crude obtained was purified by column chromatographyon silica gel using 25% ethyl acetate in petroleum ether as eluant toobtain 350 mg, 81% of the title compound as a brown oil.

LC-MS m/z 407 (M+H)⁺

b) N-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-2-aminoethanol

To a solution of3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]oxazolidin-2-one (350mg, 0.85 mmol) in 5 ml of methanol was added barium hydroxide (245 mg,1.28 mmol) taken in 5 ml of water. The reaction mixture was warmed to65° C. and stirred overnight (reaction was complete on TLC). Thereaction mixture concentrated in vacuo to remove methanol, diluted withwater and the aqueous layer was extracted with ethyl acetate. Thecombined organic fraction was washed with brine, dried over anhydrousNa₂SO₄ and concentrated to get 300 mg, 91.57% of the title compound as abrown oil, used as such in the next step.

LC-MS m/z 382.3 (M+H)⁺

c) 5-Ethyl-2-[2-fluoro-4-(2-hydroxyethylamino)-phenoxy]phenol

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene forN-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-2-aminoethanol (350mg, 0.92 mmol) and tetrahydrofurane for methanol (25 mL), the titlecompound (210 mg; 78%) was obtained as a yellow solid, afterpurification on silica gel (ethylacetate and petroleum ether: 5/5)

¹H NMR (CDCl₃), δ (ppm): 6.94 (t, J=8.9 Hz, 1H), 6.86 (d, J=1.2 Hz, 1H),6.64-6.58 (m, 2H), 6.5 (dd, J=12.6 Hz, J=2.6 Hz, 1H), 6.41 (dd, J=8.7Hz, J=2.6 Hz, 1H), 3.87 (t, J=5.1 Hz, 2H), 3.28 (t, J=5.1 Hz, 2H), 2.57(q, J=7.58 Hz, 2H), 1.21 (t, J=7.58 Hz, 3H)

LC-MS m/z 292.3 (M+H)⁺

EXAMPLE 82 5-ethyl-2-[2-fluoro-4-(propylamino)phenoxy]phenol a)4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-propylaniline

According to the procedure of example 66(a) except substitutingnicotinaldehyde for propanaldehyde (28 μl, 0.45 mmol), the titlecompound was prepared as a colorless oil (20 mg; 18%), afterpurification by preparative TLC (cyclohexane/ethyl acetate: 80/20).

MS (ES) m/e 304 (M+H)⁺

b) 5-ethyl-2-[2-fluoro-4-(propylamino)phenoxy]phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-propylaniline (20 mg, 0.066mmol), the title compound (9.4 mg, 53%) was prepared as a white solid,after purification by preparative TLC (cyclohexane/ethyl acetate:80/20).

MS (ES) m/e 290 (M+H)⁺

¹H NMR (CDCl₃) δ (ppm): 7.28 (s, 1H), 6.93 (t, 1H, J=8.8 Hz), 6.89 (d,1H, J=1.6 Hz), 6.70-6.56 (m, 3H), 3.10 (t, 2H, J=7.5 Hz), 2.60 (q, 2H,J=7.6 Hz); 1.72 (se, 2H, J=7.3 Hz), 1.22 (t, 3H, J=7.6 Hz), 1.02 (t, 3H,J=7.4 Hz)

EXAMPLE 83 2-(4-amino-2-fluorophenoxy)-5-(2-pyridin-2-yl ethyl)phenol a)4-bromo-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene

According to the procedure of example 21 (a3) except substituting4-Ethyl-2-methoxy phenol by 4-bromogualacol (2.51 mmol; 510 mg) and3-Fluoro 2-nitro pyridine by 3,4-difluoronitrobenzene (2.76 mmol; 305μL), the title compound was prepared as a clear oil in quantitativeyield (855 mg) and used without further purification.

b) 2-{[4-(2-fluoro-4-nitrophenoxy)-3-methoxyphenyl]ethynyl}pyridine

According to the procedure of example 11 (a) except substituting5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine by4-bromo-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene (0.29 mmol; 100 mg)and 3-butyn-1-ol by 2-ethynylpyridine (0.73 mmol; 73 μL), the titlecompound was prepared as a yellow solid (81%; mg) after purification onpreparative TLC (cyclohexane/ethyl acetate: 7/3).

MS (ES) m/e 365 (M+H)⁺

c) 3-fluoro-4-[2-methoxy-4-(2-pyridin-2-ylethyl)phenoxy]aniline

According to the procedure of example 20(b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene by2-{[4-(2-fluoro-4-nitrophenoxy)-3-methoxy phenyl]ethynyl}pyridine (0.23mmol; 84 mg) and THF by ethanol, the title compound was obtained as aclear oil (68%, 53 mg) after purification on preparative TLC(cyclohexane/ethyl acetate: 6/4).

MS (ES) m/e 339 (M+H)⁺

d) 2-(4-amino-2-fluorophenoxy)-5-(2-pyridin-2-ylethyl)phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for3-fluoro-4-[2-methoxy-4-(2-pyridin-2-ylethyl) phenoxy]aniline (0.16mmol; 53 mg), the title compound was prepared as a clear oil (45 mg;15%) after purification by preparative TLC(dichloromethane/methanol/ammonia: 95/5/1).

MS (ES) m/e 325 (M+H)⁺

¹H RMN (MeOD) δ (ppm): 8.46 (d, 1H, J=4.5 Hz); 7.78 (dt, 1H, J₁=7.7 Hz,J₂=1.8 Hz); 7.31-7.28 (m, 2H); 6.79 (t, 1H, J=8.9 Hz); 6.71 (s, 1H);6.56 (dd, 1H, J₁=12.7 Hz, J₂=2.6 Hz); 6.51 (s, 2H); 6.47 (ddd, 1H,J₁=8.7 Hz, J₂=2.6 Hz, J₃=1.2 Hz); 3.08-3.04 (m, 2H); 2.93-2.87 (m, 2H)

EXAMPLE 84 2-(2-aminopyridin-3yloxy)-5-ethyl-4-fluorophenol a)3-(4-bromo-5-fluoro-2-methoxyphenoxy)-2-nitropyridine

According to the procedure of example 21 (a3) except substituting4-ethyl-2-methoxyphenol by 4-bromo-5-fluoro-2-methoxyphenol (1.5 g, 5.7mmol), the title compound was prepared in 95% yield (1.85 g) afterpurification on silica gel (eluant ethyl acetate/pet ether: 1/9) as apale yellow solid.

¹H NMR (CDCl₃), δ (ppm): 8.25 (dd, J=4.48 Hz, J=1.28 Hz, 1H), 7.48 (dd,J—8.4 Hz, J=4.48 Hz, 1H), 7.28 (m, 1H), 7.18 (d, J=6.28 Hz, 1H), 7.01(d, J=8.04 Hz, 1H), 3.76 (s, 3H), LC-MS m/z 343.5 (M+H)⁺

b) 3-(5-fluoro-2-methoxy-4-vinylphenoxy)-2-nitropyridine

According to the procedure of example 57 (b) except substituting2-(4-bromo-5-fluoro-2-methoxyphenoxy)-6-fluoropyridine by3-(4-bromo-5-fluoro-2-methoxyphenoxy)-2-nitropyridine (1.7 g, 4.9 mmol),the title compound was obtained (1.1 g; 76%) after purification onsilica gel (eluant ethyl acetate/hexane: 15/85) as a pale yellow solid.

¹H NMR (CDCl₃), δ (ppm): 8.23 (dd, J=4.4 Hz, J=0.8 Hz, 1H), 7.47 (dd,J=8.4 Hz, J=4.8 Hz, 1H), 7.3 (dd, J=8.4 Hz, J=0.8 Hz, 1H), 7.08 (d,J=6.8 Hz, 1H), 6.91 (d, J=10 Hz, 1H), 6.85 (dd, J=17.6 Hz, J=11.2 Hz,1H), 5.81 (d, J=17.6 Hz, 2H), 5.43 (d, J=11.2 Hz, 3H), 3.78 (s, 3H),LC-MS m/z 290.9 (M+H)⁺

c) 3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-aminopyridine

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene by3-(5-fluoro-2-methoxy-4-vinylphenoxy)-2-nitropyridine (3.7 mmol, 1.1 g)and THF by methanol, the title compound was prepared as a white solid(800 mg; 80.5%) and used without further purification.

¹H NMR (CDCl₃), δ (ppm): 7.82 (dd, J=4.8 Hz, J=1.2 Hz, 1H), 6.89 (dd,J=8 Hz, J=1.2 Hz, 1H), 6.8 (d, J=6.8 Hz, 1H), 6.67 (d, J=10 Hz, 1H),6.57-6.6.6 (m, 1H); 4.76 (bs, 2H, D2O exchangeable), 3.82 (s, 3H), 2.66(q, J=7.6 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H) LC-MS m/z 263 (M+H)⁺

d) 2-(2-Aminopyridin-3yloxy)-5-ethyl-4-fluorophenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-aminopyridine (400 mg, 1.53mmol), the title compound was prepared in 86% yield (325 mg) as a whitesolid after washing with hexane.

¹H NMR (CDCl₃), δ (ppm): 7.85 (dd, J=5.2 Hz, J=1.2 Hz, 1H), 6.98 (d, J=8Hz, J=1.2 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.58-6.64 (m, 2H), 4.67 (bs,2H, D2O exchangeable), 2.62 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H)LC-MS m/z 249.1 (M+H)⁺

EXAMPLE 85 2-(4-acetyl-2-fluorophenoxy)-5-ethylphenylamino acetatehydrochloride a) tert-Butoxycarbonylamino-acetic acid2-(4-acetyl-2-fluoro-phenoxy)-5-ethyl-phenyl ester

To a solution of 1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone(0.37 mmol; 100 mg) in dry THF (2 mL) cooled to 0° C. were added,N-Boc-glycine (0.37 mmol; 64 mg),benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluoro phosphate(0.37 mmol; 190 mg) and triethylamine (1.09 mmol; 153 μL). The reactionwas stirred at 0° C. for 3 hours and overnight at room temperature. Themixture was concentrated, treated with saturated NH₄Cl and extractedwith dichloromethane. Combined organic phases were washed with water,dried over Na₂SO₄ and concentrated in vacuo. The title compound (91 mg;58%) was obtained as clear oil after purification on preparative TLC(cyclohexane/ethyl acetate: 7/3).

MS (ES) m/e 454 (M+Na)⁺

b) 2-(4-acetyl-2-fluorophenoxy)-5-ethylphenylaminoacetate hydrochloride

To a solution of tert-Butoxycarbonylamino-acetic acid2-(4-acetyl-2-fluoro-phenoxy)-5-ethyl-phenyl ester (0.21 mmol; 91 mg) indry dioxane (1 mL) cooled to 0° C., was added HCl/dioxane 4M (0.84 mmol;211 μL). The reaction was stirred overnight at room temperature. Aprecipitate was formed. The mixture was cooled to 0° C., filtered andthe solid was washed with diethylether. This white solid was dried invacuo to give the title compound (8%; 7 mg).

¹H RMN (MeOD) δ (ppm): 7.85 (dd, 1H, J₁=11.5 Hz, J₂=2.0 Hz); 7.78 (d,1H, J=8.7 Hz); 7.23-7.20 (m, 2H); 7.06-7.02 (m, 2H); 4.06 (s, 2H); 2.70(q, 2H, J=7.6 Hz); 2.57 (s, 3H); 1.27 (t, 3H, J=7.6 Hz).

EXAMPLE 86 1-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]-4-hydroxy butan-1-onea) 4-fluoro-N-methoxy-N-methylbenzamide

To a solution of N,O-dimethylhydroxylamine (1.51 mmol; 147 mg) in dryTHF (3 mL), under argon, was added at −78° C. nbutyllithium 2.5M (3.02mmol; 1.21 mL). The mixture was stirred minutes at −78° C., beforeaddition of 4-fluorobenzoyl chloride (1.26 mmol; 150 μL). The reactionwas stirred overnight at room temperature, then treated with saturatedNH₄Cl and extracted with ethyl acetate. Combined organic layers werewashed with water, dried over Na₂SO₄ and concentrated in vacuo, to givethe title compound (66%; 173 mg) as a yellow oil used without furtherpurification.

¹H RMN (CDCl₃) δ (ppm): 7.78 (m, 2H); 7.10 (t, 2H, J=8.7 Hz); 3.56 (s,3H); 3.38 (s, 3H).

b) 3-(1,3-dioxan-2-yl)-1-(4-fluorophenyl)propan-1-one

To a solution of 4-fluoro-N-methoxy-N-methylbenzamide (0.94 mmol; 173mg) in anhydrous THF (2 mL), at −78° C. under argon, was added asolution of (1,3-dioxan-2-ylethyl)magnesium bromide, 0.5M in THF (1.04mmol; 2.1 mL). The reaction was stirred 16 hours at room temperature.The mixture was cooled to −78° C. and (1,3-dioxan-2-ylethyl)magnesiumbromide, 0.5M in THF (2.00 mmol; 4 mL) was added again. The reaction wasstirred overnight at room temperature. The mixture was treated withsaturated NH₄Cl and extracted with ethyl acetate. The organic layer waswashed with water, dried over Na₂SO₄, and concentrated in vacuo. Thetitle compound was prepared in quantitative yield, used without furtherpurification.

MS (ES) m/e 239 (M+H)⁺

c)1-[4-(4-ethyl-2-methoxyphenoxy)phenyl]-3-(1,3-dioxan-2-yl)-1-phenylpropan-1-one

According to the procedure of example 21(a3) except substituting3-Fluoro 2-nitro pyridine by3-(1,3-dioxan-2-yl)-1-(4-fluorophenyl)propan-1-one (0.94 mmol; 401 mg),the title compound was obtained (42%, 149 mg) as a yellow oil afterpurification on preparative TLC (cyclohexane/ethyl acetate: 8/2).

MS (ES) m/e 371 (M+H)⁺

d)3-(1,3-dioxan-2-yl)-1-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]propan-1-oneand 4-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]-4-oxobutanal

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)Pyridin-3-amine for1-[4-(4-ethyl-2-methoxyphenoxy)phenyl]-3-(1,3-dioxan-2-yl)-1-phenylpropan-1-one(0.25 mmol; 91 mg), the following compounds were obtained afterpurification by preparative TLC (cyclohexane/ethyl acetate: 7/3):

-   -   3-(1,3-dioxan-2-yl)-1-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]propan-1-one        (11 mg; 13%) as a white solid

MS (ES) m/e 357 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.95 (d, 2H, J=8.9 Hz); 7.00 (d, 2H, J=8.9 Hz);6.91 (d, 1H, J=1.9 Hz); 6.87 (d, 1H, J=8.2 Hz); 6.73 (dd, 1H, J₁=8.2 Hz,J₂=1.9 Hz); 5.46 (s1, 1H); 4.66 (t, 1H, J=4.9 Hz); 4.09 (dd, 2H, J₁=10.7Hz, J₂=4.9 Hz); 3.76 (td, 2H, J₁=12.1 Hz, J₂=2.4 Hz); 3.05 (t, 2H, J=7.2Hz); 2.63 (q, 2H, J=7.6 Hz); 2.06-2.01 (m, 3H); 1.33 (d, 1H, J=13.4 Hz);1.22 (t, 3H, J=7.6 Hz).

-   -   4-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]-4-oxobutanal (12.5 mg;        17%) as a clear oil.

MS (ES) m/e 299 (M+H⁺)

e) 1-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]-4-hydroxybutan-1-one

To a suspension of NaBH₄ (0.052 mmol; 2 mg) in dry methanol, under argonat −78° C., (0.5 mL) was added4-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]-4-oxobutanal (0.040 mmol; 12 mg).The reaction was stirred 5 hours with gradual warming to −5° C., andtreated with acetic acid. The mixture was diluted with water andextracted with ethyl acetate. Combined organic layers were dried overNa₂SO₄ and concentrated in vacuo. The title compound was obtained as aclear oil (7.6 mg; 63%) after purification on preparative TLC(cyclohexane/ethyl acetate: 5/5).

MS (ES) m/e 301 (M+H⁺)

¹H RMN (CDCl₃) δ (ppm): 7.30 (d, 2H, J=8.5 Hz); 6.97 (d, 2H, J=8.6 Hz);6.89 (d, 1H, 1.9 Hz); 6.80 (d, 1H, J=8.2 Hz); 6.68 (dd, 1H, J₁=8.1 Hz,J₂=2.0 Hz); 4.70 (t, 1H, J=6.3 Hz); 3.69 (se, 2H, J=5.8 Hz); 2.61 (q,2H, J=7.6 Hz); 1.85 (q, 2H, J—6.6 Hz); 1.68 (se, 2H, J=7.0 Hz); 1.23 (t,3H, J=7.6 Hz).

EXAMPLE 87 5-Ethyl-4-fluoro-2-(2-fluoropyridin-3yloxy)phenol a)5-Ethyl-4-fluoro-2-(2-fluoropyridin-3yloxy)phenol

To a stirred solution of2-(2-aminopyridin-3yloxy)-5-ethyl-4-fluorophenol (45 mg, 0.18 mmol) inglacial acetic acid (2.5 ml) was added 0.36 ml of tetrafluoroboric acid(48% in water). The reaction mixture was cooled to 0° C. and sodiumnitrite (18 mg, 0.27 mmol) was added at 0° C. and stirred at 0° C. for1.5 hours until reaction was complete on TLC. The reaction mixture wasquenched by adding ice and sodium bicarbonate solution and stirred for10 minutes before extracting the aqueous solution with ethylacetate. Thecombined ethyl acetate fraction was washed with saturated sodiumbicarbonate solution, water, followed by brine, dried over anhydroussodium sulfate and concentrated in vacuo to get the crude compound. Thecrude material was column purified over silica gel using Petroleumether/ethyl acetate 9:1 as eluant and then further purified bypreparative HPLC using 0.1% TFA in water and acetonitrile as solventsystem to get 8 mg (17.6%) of5-Ethyl-4-fluoro-2-(2-fluoropyridin-3yloxy)phenol as a white solid.

¹H NMR (CDCl₃), δ (ppm): 8.01-8.98 (m, 1H), 7.43-7.39 (m, 1H), 7.17-7.20(m, 1H), 6.91 (d, J=7.2 Hz, 1H), 6.57 (d, J=9.6 Hz, 1H), 5.35 (s, 1H,D2O exchangeable), 2.63 (q, J=7.5 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H)

LC-MS m/z 252 (M+H)

Alternatively the title compound can be synthesized from3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-aminopyridine of step c) ofexample 84 according to following steps:

b) 3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-fluoropyridine

To a stirred solution of3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-aminopyridine (1.5 g, 5.7 mmol)in glacial acetic acid (10 ml) was added 12 ml of tetrafluoroboric acid(48% in water). The reaction mixture was cooled to 0° C. and sodiumnitrite (590 mg, 8.5 mmol) was added at 0° C. and stirred at 0° C. for45 minutes until reaction was complete on TLC. Formation of 2 compoundswas observed on the TLC. The colourless reaction mixture turned paleyellow and then to deep yellow during this time. The reaction mixturewas quenched by adding ice and sodium bicarbonate solution and theaqueous solution was extracted with ethyl acetate. The combined ethylacetate fraction was washed with water, followed by brine, dried overanhydrous sodium sulfate and concentrated in vacuo to get the crudecompound. The crude material was column purified over silica gel usingpet ether/ethyl acetate 9:1 as eluant to obtain the first fractionyielding 610 mg, 40.39% of the title compound3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-fluoro pyridine as a colourlessliquid. The column was then eluted with 100% ethyl acetate to collectthe second fraction that gave 620 mg, 41.3% of the3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-pyridin-2-ol.

3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-fluoropyridine

¹H NMR (CDCl₃), δ (ppm): 7.90-7.89 (m, 1H), 7.20 (t, J=8 Hz, 1H),7.1-7.07 (m, 1H), 6.82 (d, J=6.96 Hz, 1H), 6.73 (d, J=9.68 Hz, 1H), 3.8(s, 3H), 2.67 (q, J=7.53 Hz, 2H), 1.25 (t, J=7.58 Hz, 3H)

LC-MS m/z 266.2 (M+H)⁺

3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-pyridin-2-ol

¹H NMR (CDCl₃), δ (ppm): 7.15 (d, J=6.44 Hz, 1H), 6.82-6.78 (m, 2H),6.72 (d, J=7.2 Hz, 1H), 6.17 (t, J=7.2 Hz, 1H), 3.81 (s, 3H), 2.67 (q,J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H) LC-MS m/z 264.1 (M+H)⁺

c) 5-Ethyl-4-fluoro-2-(2-fluoropyridin-3yloxy)phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine by3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-fluoro pyridine (610 mg, 2.3mmol), the title compound was prepared in 81% yield (470 mg) as a whitesolid after washing with hexane.

EXAMPLE 88 N-Ethyl-4-(4-ethyl-2-hydroxy-phenoxy)-3-fluoro benzenesulfonamide a) 4-(2-Benzyloxy-4-ethyl-phenoxy)-N-ethyl-3-fluoro-benzenesulfonamide

According to the procedure of example 70(a) except substitutingN-Acetylethylenediamine for ethylamine.HCl ((8.4 mmol; 700 mg), thetitle compound (402 mg; 0.94 mmol; 25%) was obtained as a yellow oil,after purification on silica gel (gradientcyclohexane/dichloromethane/ethyl acetate).

MS (ES) m/e 430 (M+H)⁺

b) N-Ethyl-4-(4-ethyl-2-hydroxy-phenoxy)-3-fluoro benzene sulfonamide

According to the procedure of example 20 (b) except substituting4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for4-(2-Benzyloxy-4-ethyl-phenoxy)-N-ethyl-3-fluoro-benzene sulfonamide(402 mg; 0.94 mmol) and tetrahydrofurane for ethanol (4 mL), the titlecompound (140 mg; 44%) was obtained as a clear oil, after purificationon preparative TLC (dichloromethane).

MS (ES) m/e 340 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 7.63 (d, 1H, J=10.0 Hz); 7.53 (d, 1H, J=8.7 Hz);6.95 (d, 1H, J=8.2 Hz); 6.92 (s, 1H); 6.87 (d, 1H, J=8.2 Hz); 6.74 (d,1H, J=8.2 Hz); 6.03 (br, 1H); 5.01 (t, 1H, J=5.9 Hz); 3.00 (qt, 2H,J=7.0 Hz); 2.62 (q, 2H, J=7.6 Hz); 1.23 (t, 3H, J=7.6 Hz); 1.10 (t, 3H,J=7.3 Hz).

EXAMPLE 89 5-[(3-fluoropyridin-4-yl)methyl]-2-[(6-fluoropyridin-2-yl)oxy]phenol a)[4-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-(3-fluoro-pyridin-4-yl)-methanol

To a solution of 3-fluoropyridine (2.3 mmol; 220 mg), under argon, inanhydrous THF (1 mL) cooled to −78° C., was added nBuLi (2.3 mmol; 1mL). The reaction was stirred 1 hr at −78° C. then a solution ofvanilline-OTBS (2.3 mmol; 600 mg) in THF (1 mL) was added. The reactionwas allowed to warm up to room temperature overnight. Hydrolysed byNH₄Cl sat. (3 mL), the mixture was extracted with dichloromethane (3 mL)and ethyl acetate (2*3 mL). Combined organic phases were dried overMgSO₄, concentrated to yield a light brown solid. Heating in diethylether, then filtering afforded the title compound as a white solid (125mg; 0.34 mmol; 15%) used without further purification.

MS (ES) m/e 364 (M+H)⁺

b) 4-[(3-fluoropyridin-4-yl)methyl]-2-methoxyphenol

Pd/C (0.02 mmol; 40 mg) was added to a solution of[4-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-(3-fluoro-pyridin-4-yl)-methanol(0.19 mmol; 70 mg) in methanol (2 mL) and H₂SO₄ (0.5 mL). The mixturewas flushed twice with hydrogen, and the reaction was stirred overnightat 35° C. The mixture was filtered on celite, washed with methanol.After concentration, water was added (3 mL) and K₂CO₃ until pH 8. Theaqueous phase was extracted with ethyl acetate (2*3 mL). Combinedorganic phases were dried over MgSO₄, concentrated to yield the titlecompound as a white solid (32 mg; 0.14 mmol; 71%) used as such.

MS (ES) m/e 234 (M+H)⁺

c)2-fluoro-6-{4-[(3-fluoropyridin-4-yl)methyl]-2-methoxyphenoxy}pyridine

According to the procedure of example 21(a3) except substituting4-Ethyl-2-methoxy phenol for4-[(3-fluoropyridin-4-yl)methyl]-2-methoxyphenol (60 mg; 0.26 mmol), thetitle compound (85 mg; 100%) was prepared as a brown oil, used withoutany purification.

MS (ES) m/e 329 (M+H)⁺

d) 5-[(3-fluoropyridin-4-yl)methyl]-2-[(6-fluoropyridin-2-yl)oxy]phenol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for2-fluoro-6-{4-[(3-fluoropyridin-4-yl)methyl]-2-methoxyphenoxy}pyridine(85 mg; 0.26 mmol), the title compound (23 mg; 28%) was prepared as aclear oil, after purification by preparative TLC (dichloromethane/ethylacetate).

MS (ES) m/e 315 (M+H)⁺

¹H RMN (CDCl₃) δ (ppm): 8.37 (s, 1H); 8.27 (d, 1H, J=4.7 Hz); 7.76 (q,1H, J=8.0 Hz); 7.12 (t, 1H, J=5.7 Hz); 7.06 (d, 1H, J=8.2 Hz); 6.83 (d,1H, J=1.8 Hz); 6.79-6.75 (m, 2H); 6.62 (dd, 1H, J₁=7.9 Hz, J₂=2.1 Hz);3.98 (s, 2H).

EXAMPLE 90 3-(4-Ethyl-5-fluoro-2-hydroxyphenoxy)-pyridin-2-ol

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-pyridin-2-ol (50 mg, 0.19 mmol),the title compound (25 mg; 53%) was prepared as a white solid, afterwashing with hexane twice and with diethylether MS (ES) m/e 315 (M+H)⁺

¹H NMR (CD₃OD), δ (ppm): 7.18 (d, J=6.5 Hz, 1H), 6.96 (d, J=7.4 Hz, 1H),6.81 (d, J=7.4 Hz, 1H), 6.74 (d, J=10.1 Hz, 1H), 6.32 (t, J=6.98 Hz,1H), 2.6 (q, J=7.5 Hz, 2H), 1.2 (t, J=7.5 Hz, 3H)

LC-MS m/z 250 (M+H)⁺

EXAMPLE 912-amino-N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]ethanesulfonamidea) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid[4-(4-ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-amide

According to the procedure of example 42(a) except substituting3-chloropropanesulfonyle chloride by 2-phtalimido ethanesulfonylchloride (0.46 mmol; 125 mg), the title compound (77%; 147 mg) wasobtained as a white gum after purification on preparative TLC(cyclohexane/ethyl acetate: 6/4).

MS (ES) m/e 499 (M+H)⁺

b) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid[4-(4-ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl]-amide

According to the procedure of example 1 (b) except substituting6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine for2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethane sulfonic acid[4-(4-ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-amide (0.30 mmol; 147mg), the desired compound was prepared in 55% yield (79 mg) afterpurification by preparative TLC (cyclohexane/ethyl acetate: 7/3).

MS (ES) m/e 485 (M+H⁺)

¹H RMN (CDCl₃) δ (Ppm): 7.86 (dd, 2H, J₁=5.5 Hz, J₂=3.1 Hz); 7.75 (dd,2H, J₁=5.4 Hz, J₂=3.0 Hz); 7.43 (s, 1H); 7.23 (dd, 1H, J, =11.5 Hz,J₂=2.4 Hz); 7.01 (d, 1H, J=8.8 Hz); 6.93 (t, 1H, J=8.6 Hz); 6.88 (d, 1H,J=1.77 Hz); 6.71 (d, 1H, J=8.2 Hz); 6.65 (dd, 1H, J₁=8.3 Hz, J₂=1.9 Hz);5.82 (s1, 1H); 4.15 (t, 2H, J=6.3 Hz); 3.48 (t, 2H, J=6.2 Hz); 2.59 (q,2H, J=7.6 Hz); 1.22 (t, 3H, J=7.6 Hz).

c)2-amino-N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]ethanesulfonamide

According to the procedure of example 39 except substituting2-{3-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-1,3-dioneby 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid[4-(4-ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl]-amide (0.13 mmol; 64mg), the title compound was obtained as a yellow oil (20%, 10 mg) afterpurification on preparative TLC (dichloromethane/methanol/ammonia:90/10/1).

MS (ES) m/e 355 (M+H)⁺

¹H RMN (MeOD) δ (ppm): 7.22 (dd, 1H, J, =12.3 Hz, J₂=2.5 Hz); 6.99 (d,1H, J=8.8 Hz); 6.84-6.79 (m, 2H); 6.74 (d, 1H, J=8.2 Hz); 6.64 (dd, 1H,J, =8.2 Hz, J₂=1.9 Hz); 3.25 (t, 2H, J=6.7 Hz); 3.10 (t, 2H, J=6.5 Hz);2.57 (q, 2H, J=7.6 Hz); 1.21 (t, 3H, J=7.6 Hz).

FabI Inhibition:

The compounds of the present invention are useful inhibitors ofbacterial FabI enzyme.

Compound inhibitory activity of FabI enzyme is measured in vitro by theIC50 determination using a fluorescent based assay.

The protein FabI from E. coli is prepared and purified using standardmethods for recombinant protein expression after cloning of the gene ina prokaryotic expression vector.

The biochemical activity of the FabI enzyme is assessed using thefollowing method.

The assay buffer “AB” contains 50 mM Hepes pH7.5, 100 μM Dithiothreitol,0.006% Triton-X100. The following components are added in a blackpolystyrene Costar plate up to a final volume of 55 μL: 1.5 μL DMSO, orinhibitor dissolved in DMSO and 53.5 μL of a FabI/NADH/NAD+ mixture inAB. After 60 min of pre-incubation at room temperature, the reaction isstarted by addition of 5 μL of Crotonoyl-CoA to a final volume of 60 μL.This reaction mixture is then composed of 40 nM FabI (produced in housefrom E. coli, C-terminal 6-His tagged), 20 μM NADH (Biochemika), 10 μMNAD+ (Biochemika), 50 μM Crotonoyl-CoA (Biochemika) and compound atdefined concentration. Fluorescence intensity of NADH (l_(ex)=360 nm,l_(em)=520 nm) is measured immediately after Crotonoyl-CoA addition, and2 hours later by a Fluostar Optima (BMG). Enzyme activity isproportional to the signal decrease from which inhibition percentagesare derived. For IC₅₀ determinations, the inhibitor is tested at 6 to 10different concentrations, and the related inhibitions are fitted to aclassical langmuir equilibrium model using XLFIT (IDBS).

In Vitro Inhibition of Recombinant E. coli FabI Enzyme by SelectedCompounds of Formula (I).

Examples IC₅₀ (μM)  5 0.97 16 0.51 21 0.069 25B 0.57 27 0.47 28 0.85 290.15 37 0.41 48 1 50 0.3 55 0.092 57 1.1 64 0.13 71 0.33 84 0.1 85 0.1187 0.031

Antibacterial Activity

The compounds of the present invention are useful antibacterial agentshaving a selective spectrum of activity in vitro against standardbacterial strains which are used to screen for activity againstpathogenic bacteria. Notably the compounds of the present invention showactivity against Staphyloccus aureus including multiresistant strainsand Echerichia coli. The activity is presented as Minimum InhibitoryConcentration (MIC) expressed in μg/ml.

Whole-cell antimicrobial activity was determined by broth microdilutionmethod in microtiterplates. The compound was tested in serial 4-folddilutions ranging from 0.06 to 64 mcg/mL. Test organisms were selectedfrom the following laboratory strains: Staphylococcus aureus CIP 76.25,Staphylococcus aureus BAA39 MDR, Staphylococcus aureus NEM 14157 PeniR,Staphylococcus aureus CIP 54.146, Escherichia coli CIP 76.24. Bacteriawere tested in Tryptic Soy (TS) or Mueller Hinton (MH) broth using aninoculum of 10⁴ to 10⁶ UFC/mL incubated at 37° C. for 20 h.

The minimum inhibitory concentration (MIC) was determined as the lowestconcentration of compound at which no visible bacteria growth isobserved (90% inhibition of absorbance of at 600 nM.)

Representative Examples of MIC (μg/ml)

Compound E. coli S. aureus S. aureus S. aureus Example N° CIP 76.24 CIP76.25 BAA39MDR NEM14157 Triclosan 0.25 0.125  1 16 1 1 0.25  3 4 0.250.25 0.25  5 4 0.25 0.25 0.25  6 16 1 1 1  7 >16 2 16 4 0.25 0.25 0.2521 0.25 0.25 0.25 0.25 27 4 0.25 0.25 0.25 25A 16 0.25 25B 4 0.062 0.0620.062 29 1 0.062 0.062 0.062 32 16 4 34 1 0.25 0.25 0.25 35 1 0.25 37 40.062 0.25 0.25 38 4 0.062 0.25 1 39 16 1 1 1 47 16 0.25 48 4 0.062 5216 1 55 1 0.25 57 4 0.25 62 4 0.25 64 1 0.25 0.062 0.062 65 1 0.25 66 160.25 67 16 0.25 70 16 0.25 71 4 <0.062 0.25 0.062 74 4 0.062 0.062 0.06279 16 0.25 0.25 0.25 81 4 0.25 82 16 0.25 84 0.25 0.25 0.25 0.25 85 10.062 86 4 0.062 0.062 0.062 87 0.25 0.062 0.062 0.016

In Vitro Activities Against Resistant Stains of S. aureus

MIC (μg/ml) S. S. S. S. S. S. aureus aureus aureus aureus aureus aureusUSA300 1651 1652 2012 2018 MRSA* MRSA* LRSA* LRSA VISA VISA* Vancomycin1 0.5 1 1 8 4 Example 21 0.12 0.5 0.12 0.5 0.12 0.25 Example 48 0.06 0.50.12 0.5 0.12 0.25 MRSA = Methicillin Resistant S. aureus; LRSA =Linezolid resistant S. aureus; VISA = Vancomycin Resistant S. aureus;

In Vivo Antibacterial Activity of Compounds

An experimental model of infection by S. aureus was used to assess theantibacterial activity of FabI inhibitors.

Briefly in vivo studies were performed using 5-6-week-old femaleBALB/c@Rj mice as follows Groups of six mice are used for eachcondition.

The virulent strain of Staphylococcus aureus CIP 54.146 is grown toexponential phase in Tryptic soy (TS) broth culture. The bacterialculture is diluted to obtain a bacterial suspension of 1·10⁸ UFC/ml.Then 200 μl of the suspension is administered by intraperitonealinjection to each mouse, this infecting dose has been determined to bethe LD90 (Lethal dose 90%). The inoculums count was determined byplating 10-fold dilutions of the suspension on TH agar platesimmediately after inoculation.

Compounds to be assessed are dissolved and diluted in an aqueoussolution containing 15% cyclodextrin and 200 μl of the solution isinjected sub cuteanously to each mice, just after the infection.

For 48 hours post-infection, mice are monitored and survival recorded at18 h and 24 h postinfection. The negative control group receives the 15%cyclodextrin solution alone and vancomycin at 10 mg/kg is used as thepositive control.

All animal experiments were carried out in accordance with institutionalguidelines. Compound activity is measure by its effect at a given doseon the percentage of surviving animal.

As shown in FIGS. 1 and 2 results obtained with compound derivative ofthe formula are able to protect mice against the lethal effect ofbacterial multiplication.

Example of Pharmaceutical Composition

An injectable preparation was prepared comprising 500 mg of a compoundof example 87 and sufficient quantity of aqueous sterile excipient forpreparing 10 to 50 ml of injectable solution.

Tablets have been prepared containing:

-   -   300 mg of compound of example 21    -   Sufficient quantity of exipient for a 1 g tablet        -   Detail of the excipient, starch, talc, magnesium stearate

We claim:
 1. A method of treatment of microbial infection whichcomprises administering to a patient in need thereof an effective amountof a hydroxyphenyl derivative of formula (I)

R1 is phenyl or a 6 membered monocyclic nitrogenous heteroaryl offormula

Z4, Z5, Z6, Z7 and Z8 are independently C or N with a maximum of threeN, R1 being possibly substituted by 1 to 3R identical or different, Rbeing selected from the group comprising H, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, 5 or 6 membered monocyclic heteroaryl or aliphaticheterocycle containing 1 to 3 heteroatoms selected from N, O and S,COOR_(a), COR_(a), CONR_(a)R_(b), OCOR_(a), CN, OR_(a), NR_(a)R_(b),CR_(a)═NOR_(b), NR_(a)COR_(b), NR_(a)COOR_(b), OCONR_(a)R_(b),NR_(a)CONR_(b)R_(c), SR_(a), SO₂R_(a), SO₂NR_(a)R_(b), NR_(a)SO₂R_(b)and NR_(a)C(S)NR_(b)R_(c), all being possibly substituted by R′, or R isC₁-C₄fluoro-alkyl, or R is fluoro when R1 is phenyl, or R is halogenowhen R1 is nitrogenous heteroaryl, R2 is phenyl, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₁-C₄fluoro-alkyl, C₂-C₄fluoro-alkenyl, OR_(a),SR_(a), all being possibly substituted by 1 to 3 identical or differentR′, R_(a), R_(b) and R_(c), identical or different, are selected fromthe group consisting of H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,phenyl, heteroaryl and aliphatic heterocycle as defined above for R2,the heteroaryl and the heterocycle being possibly formed with the carbonand nitrogen atoms to which R_(a), R_(b) and R_(c) are linked, R′ isselected from the group comprising heteroaryl and aliphatic heterocycleas defined above for R2, C₁-C₈ alkyl, CH₂CO₂R″, CO₂R″, COR″, CONR″R′″,OCOR″, OR″, NR″R′″, NR″COR′″, NR″COOR′″, OCONR″R′″, NR″CONR″R′″,NR″SO₂R′″, SO₂R″, NR″SO₂R′″, halogen and CN, R″ and R′″, identical ordifferent, are H, C₁-C₈ alkyl or form together a 4 to 6 memberedheterocycle with 1 to 3 heteroatoms selected from N, O and S, Yrepresents H or a labile chemical group able to regenerate in vivo thefree phenol selected from the group consisting of C(O)R_(a), C(O)OR_(a),C(O)NR_(a), R_(b), P(O)(OH)₂ and COCHR_(a)NR_(b)R_(c), Z1 and Z3,identical or different, are halogen or H, Z2 is fluoro or H, providedthat either Z2 is fluoro and all the other definitions are as definedabove, or Z6 is a carbon atom substituted by R as defined above, R beingdifferent from H, alkyl, halogen, NH₂, OH, CONH₂ or fluoro alkyl and allthe other definitions are as defined above, or Z4 or Z5, or Z7 or Z8 arecarbon atoms substituted by NR_(a)R_(b) or OR_(a), OR_(a) beingdifferent from OH and all the other definitions are as defined above, orZ5, or Z7, is a carbon atom substituted by R, R being different from Hand all the other definitions are as defined above, or R2 is aC₁-C₈alkyl-heteroaryl radical or a C₁-C₈alkyl-OR_(a) radical, OR_(a)being different from OH and all the other definitions are as definedabove, or a pharmaceutically acceptable organic or mineral salt, as wellas the racemic derivatives and each unique not racemic derivatives, incase the derivatives of formula (I) have one or more chiral centers,both the cis (Z) and trans (E) isomers, in cases the derivatives offormula (I) have unsaturated carbon=carbon double bonds, and any N-oxideform of the derivatives.
 2. The method according to claim 1, wherein R1is a 6 membered monocyclic heteroaryl with 1 or 3 nitrogen atomsselected from the group consisting of pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl and triazinyl.
 3. The method according to claim1, wherein R1 is a phenyl.
 4. The method according to claim 1, whereinR1 is substituted by 1 to 3 substituents selected from the groupcomprising F, COR_(a), OR_(a), NR_(a)R_(b), alkynyl, SO₂R_(a),NR_(a)SO₂R_(b), SO₂NR_(a)R_(b), NR_(a)COOR_(b) and CR_(a)═NOR_(b). 5.The method according to claim 1, wherein Z2 is fluoro.
 6. The methodaccording to claim 1, wherein Z6 is a carbon atom substituted by R, Rbeing different from H, alkyl, halogen, NH₂, OH, CONH₂ or fluoro alkyl.7. The method according to claim 1, wherein Z4 or Z5, or Z7 or Z8, arecarbon atoms substituted by NR_(a)R_(b) or OR_(a).
 8. The methodaccording to claim 1, wherein, Z5 or Z7 is a carbon atom substituted byR, R being different from H.
 9. The method according to claim 1, whereinR2 is a C₁-C₈alkyl-heteroaryl or C₁-C₈alkyl-OR_(a).
 10. The methodaccording to of claim 1, wherein Y represents H.
 11. The methodaccording to claim 1, wherein Y represents a labile chemical groupselected from the group consisting of C(O)R_(a), CO(O)R_(a),C(O)NR_(a)R_(b), P(O)(OH)₂ and COCHR_(a)NR_(b)R_(c).
 12. The methodaccording to claim 1, wherein R2 is C₁-C₈ alkyl.
 13. A method oftreatment of microbial infection which comprises administering to apatient in need thereof an effective amount of a hydroxyphenylderivative of formula (I)

R1 is phenyl substituted by 1 to 3R identical or different, R beingselected from the group comprising H, fluoro, C₁-C₈ alkyl, C₁-C₄fluoro-alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, COOR_(a), COR_(a),CONR_(a)R_(b), OCOR_(a), CN, OR_(a), NR_(a)R_(b), CR_(a)═NOR_(b),NR_(a)COOR_(b), OCONR_(a)R_(b), NR_(a)CONR_(b)R_(c), SR_(a), SO₂R_(a),SO₂NR_(a)R_(b) and NR_(a)C(S)NR_(b)R_(c), R2 is C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₁-C₄fluoro-alkyl, C₂-C₄fluoro-alkenyl, OR_(a)or SR_(a), R_(a), R_(b) and R_(c), identical or different, are selectedfrom the group consisting of H, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl; Y represents H, Z1 and Z3 are both H, Z2 is fluoro, or apharmaceutically acceptable organic or mineral salt, as well as theracemic derivatives and each unique not racemic derivatives, in case thederivatives of formula (I) have one or more chiral centers, both the cis(Z) and trans (E) isomers, in cases the derivatives of formula (I) haveunsaturated carbon=carbon double bonds, and any N-oxide form of thederivatives.
 14. The method of claim 13, wherein R1 is phenyl and R isfluoro.
 15. The method of claim 1, wherein said microbial infection isan infection by E. coli, S. aureus, M. tuberculosis, H. pylori orPlasmodium falciparum.
 16. The method of claim 13, wherein saidmicrobial infection is an infection by E. coli, S. aureus, M.tuberculosis, H. pylori or Plasmodium falciparum.